Prior to an important conference at U.N.C.L.E. headquarters, a bizarre series of events occurs revolving around a strange man Mr. Hemmingway (Richard Haydn) who keeps appearing and disappearing at will in the building. Solo and Illya learn that he has been placed there by Waverly to test the security system, but THRUSH also has an inside agent, Riley (Peter Haskell), who plants an exploding false tabletop on the conference table at the direction of Dr. Egret (Lee Meriwether). Solo has only a few minutes, before the conference is to begin, to try and find out who the infiltrator is.

Solo and Illya devise a clever scheme to discredit a Balkan intelligence chief (Werner Klemperer) with a bogus secret gas. With the help of a bankrupt exterminator (William Shatner) and his wife, Illya poses as a fellow countryman and exploits the paranoia of the chief and his bumbling assistant (Leonard Nimoy).

U.N.C.L.E. must transport captured THRUSH official Egon Stryker (Ralph Taeger) from New York to Washington with THRUSH rescuing him. While Waverly takes a decoy along one route, Solo and Illya take the real Stryker. Or is it ? But in a mixup, Fran Parsons (Joanna Moore),a secretary on her lunch hour, gets handcuffed to Stryker and has to go along.

U.N.C.L.E. Portuguese translator Mandy Stevenson (Barbara Feldon) hungers for more excitement, so Solo sends her on a fake mission to get Waverly's tobacco not realizing she has taken an important microfilm that THRUSH is after. Solo, Illya and THRUSH pursue her through the streets of Manhattan, and eventually she and Solo are captured by the THRUSH leader, Victor Gervais (Cesar Romero), and Solo has to use his skills as a marksman to escape.

Solo gets an unwelcome young companion (Kurt Russell), a ten year old who wants Solo to marry his widowed mother, in his efforts to find the source of a deadly chemical that killed an entire Scottish village. In a race to find the source with General Yokura (Leonard Strong), Solo eventually uses a ring on the finger of a statue to pinpoint a cave where the deadly chemical has leaked from, but has to use his wits to escape when he is trapped there by Yokura and his men.

U.N.C.L.E. and Thrush agents compete to gain possession of a mind-reading device created by a magician who has been murdered by Thrush.

THRUSH agent Elom tries to kidnap a geologist who has developed an earthquake activating machine, but mistakes debt-ridden salesman Buzz Conway for the scientist. Solo and Illya let THRUSH go on thinking Conway is the scientist, while Elom lets his attraction for THRUSH agent Narcissus Darling interfere with his judgment. Conway is captured, and Solo and Illya must rescue him and find the machine.

When a minor European leader is assassinated, Solo steals a medallion from his body containing a microdot listing the THRUSH agents in the country, but must elude the secret police and outwit intelligence agent Satine (Ricardo Montalban), who also wants the medal. Teacher and tour guide Sara Taub (June Lockhart) and her high school students are used by Solo to try and sneak the medal over the border.

Solo and Illya try to protect Professor Lillian Stemmler from THRUSH after she invents a drug called Plus X, which heightens all the human senses. Unbeknownst to them, she is a THRUSH agent herself who at first cooperates willingly, then has second thoughts. But THRUSH agent Rollo kidnaps her daughter Leslie and forces her to cooperate. The drug is given to three THRUSH agents who will attack a U.S. government plutonium plant using their superior senses, while at the same time the guards will be given a dose of Minus X, which dulls the senses.

While in Italy investigating a THRUSH plan to divert the Gulf Stream with heavy water, Solo finds himself eluding THRUSH guards, and ends up hiding under the bed of Pia Monteri. Solo escapes a shotgun wedding, the family feels Pia's honor has been compromised, and the girl's American uncles retired Prohibition-era gangsters ""Fingers"" Stilletto, Enzo ""Pretty"" Stilletto, and Federico ""Feet"" Stilletto are called. At the island headquarters of Louis Strago, Illya is tortured by Strago's sadistic female assistant, Miss Diketon. Solo joins forces with the Stilletto brothers to try and rescue him.

Waverly's cousin is killed by his own dog when he refuses to sell his stock to a gypsy named Delgrovia (Paul Lambert), so Illya investigates and, with the help of Ursula (Susan Oliver) and dog expert Guido Panzini (Pat Harrington Jr.), traces two of the dogs to Delgrovia's estate, where he and Ursula are soon cornered by a pack of deadly Doberman pinschers.

Waverly is poisoned, and taken to a hospital where he is subjected to the rays of a brain-altering machine by THRUSH agent Dr, Dabree (Elsa Lanchester) designed to make him ineffective without killing him. While investigating others who have suffered the same fate, Solo finds Cecille Bergstrom (Yvonne Craig) and together they try to unravel the mystery and save Waverly.

Squire G. Emory Partridge (George Sanders) kidnaps Illya and lures Solo to his manor in order to kill them off in his dungeon torture chamber in revenge for a past encounter. But Peggy Durance (Bonnie Franklin) helps them escape, with the unintended aid of Partridge's bumbling wife Edith (Jeanette Nolan).

Solo and Illya board the Adriatic Express train on New Year's Eve to intercept Madame Nemirovitch, a THRUSH agent who is carrying a chemical that is capable of stopping the reproductive process. Eva, a young girl who delivers a message to Madame Nemirovitch as the train leaves, is caught on board. Throughout the evening, the THRUSH agent and Solo and Illya engage in a battle of wits as the train speeds along its route.

When secret ""File 40"" documents turn up outside headquarters, Waverly assigns Solo and Illya to find out if George Donnell is a double agent. Carla Drosten is too anxious to accuse Donnell and Solo must use special ""Waverly rings"" to try and expose the real double agent.

Retired U.N.C.L.E. agent Albert Sully (Martin Balsam) is brought back to impersonate a crime syndicate leader, and insists on leaving Solo and Illya behind and running the operation himself. He reunites with wartime fellow agent and old flame Bryn Watson (Barbara Shelly) and tracks down a secret crime conference, with the exasperated Solo and Illya trying to keep him from being killed in the process.

THRUSH eastern in Japan acquires a volcano-activating device, and Solo and Illya, along with Cricket Okasada, a film student, infiltrate a toy store and a karate school to find it. THRUSH leader Mr. Kutuzov oversees local THRUSH head Harada in the operation, and Solo finds himself fighting for his life against a life size sword wielding puppet.

A top-level U.N.C.L.E. conference is to be held in Switzerland, but a nearby boys' school is actually a THRUSH front run by Mother Fear and Dennis Jenks that is training its students to be assassins. Solo is captured by the boys, and, when he refuses to reveal the conference location, is forced to operate the controls of two electric trains so they do not collide with each carrying a vial of deadly nerve gas. Illya and Anna Paola, a social worker who resent children, are also captured. The escape, and arrive at the conference just as the boy's choir is ready to kill Waverly and the others with THRUSH rifles from under their robes.

In spoof of ""My Fair Lady,"" Solo is recuperating from a fall into a Venice canal, Illya teams with Mark Slate to uncover Baroness Bibi de Chasseur, a THRUSH money courier who has contact with the treasurer of THRUSH. They recruit a barroom entertainer, Rosy Shlagenheimer, an exact double, to impersonate her. The switch is made, but in the confusion the Baroness makes another switch and poses as Rosy, then finds herself falling in love with Slate.

Illya recuperating in the hospital, is kidnapped by an old enemy, Viktor Karmak (Darrin McGavin), to lure Solo into a trap. Solo follows a clue to a twelve block condemned area of Manhattan, and finds modern artist Sheila Van Tillson (Marlyn Mason). Karmak appears and announces that Solo has until dawn to find Illya before a deadly gas kills him, while Karmak and his pet jaguar will try to hunt Solo down at the same time.

The conuation of "The Quadripartite Affair". Gervaise Ravel (Anne Francis) returns and Solo and Illya again enlist Marion Raven (Jill Ireland) to help them pursue her through the Andes, where the treachery of police lieutenant Manuera (James Frawley) impedes their efforts to capture Ravel.

The 'Re-collectors' claim to be trying to locate works of art stolen by the Nazi's but all is not as it appears.

While in Italy investigating a THRUSH plan to divert the Gulf Stream with heavy water, Solo finds himself eluding THRUSH guards, and ends up hiding under the bed of Pia Monteri. Solo escapes a shotgun wedding, the family feels Pia's honor has been compromised, and the girl's American uncles retired Prohibition-era gangsters ""Fingers"" Stilletto, Enzo ""Pretty"" Stilletto, and Federico ""Feet"" Stilletto are called. At the island headquarters of Louis Strago, Illya is tortured by Strago's sadistic female assistant, Miss Diketon. Solo joins forces with the Stilletto brothers to try and rescue him.

Oliver Barnes (Lawrence Mantaigne), a THRUSH agent, unsuccessfully tries to destroy a package. Solo and Illya suspect a connection between this and a new ""molecutronic gun"" developed by Dr. Fabray (William Marshall). Solo runs into Abbe Nelton (Anna Capri). Fabray turns out to be a THRUSH collaborator. The entire scheme was a plan to get Illya to take the ""gun"" actually a bomb, into U.N.C.L.E. headquarters in Trojan Horse fashion.

On vacation Solo is asked by an old love interest, Clara Valdar (Madlyn Rhue) to help her smuggle Gypsy leader Emil (Jacques Aubuchon) out of Terbuf with evidence that the corrupt head of the secret police, Colonel Morisco (Alan Caillou), has been embezzling foreign aid money with the aid of the repulsive Major Vicek (Albert Paulsen).