The four Paradine brothers all meet their deaths in London, Paris, Berlin, and Madrid. Explosives go off, killing each one of them.
Artemus Gordon is in Chicago writing, producing, and starring in his own play when a Secret Service agent, Joseph, arrives to inform the ex-agent that they need Artie to return to duty to deal with Professor Albert Paradine the Second, an even greater criminal genius than his father. When Artie refuses, insisting he wants to pursue his career on stage, Joseph points out that the it appeared the audience was ready to rip him apart. Despite that, Artie says that he will only come back if Jim does, and Jim swore that the Loveless case would be his last.
In Mexico, Jim is trying to hold off scorned lover Juanita and her three brothers. Secret Service agent Edward Jensen arrives and tells him that the government has a risky mission for him. Jim immediately accepts rather than stick around and the two men ride off.
Jim and Artie are reunited in Washington and Artie is unhappy that he had to keep his word, since he figured that Jim would keep his word and never come back. Jim claims that he's only doing it because his country needs him, and they meet with Robert T. "Skinny" Malone, Secret Service director. Malone wants them back because their adventures have seen print in a tell-all book and the reading public want them back. Paradine has disappeared and no one knows what he wants, but rumor has him in Parsons Ridge, NV. Malone tells the agents to go there and stop Paradine from whatever he's doing, and puts them on a strict training regimen while their train, the Wanderer, is refurbished.
The agents are soon done with their training and head for the train station, but Juanita and her brothers rope the agents and drag them down the street. The brothers then attack Jim while Artie borrows a two-seated bicycle from a passing couple and rescues his partner. As the two agents ride off, Artie realized why Jim really wanted to leave Mexico. Once they depart aboard the Wanderer, Jim explains that he doesn't plan to see Juanita or her brothers ever again.
When the train arrives in Parsons Ridge, Paradine is at the station to meet the agents. He offers them champagne at a local saloon and tells them that he's been tracking them every step of the way. At the saloon, Paradine admits that he killed his brothers because they were decent and hard-working, and now he plans to conquer the world by turning the major nations against each other and setting off what he plans are the first of two "world wars." When Jim and Artie try to capture him, Paradine uses a handheld invisibility device to disappear. He tells them to go back to tell Malone that there's no stopping him and they might as well surrender. After Paradine slips away, his two saloon girls, twins Yvonne and Daphne, tell the agents that Paradine often turns invisible to spy on the dance girls in their changing rooms. An enormous explosion shakes the town and the twins explain that Paradine likes to test his new explosives.
The agents return to Washington and brief Malone, warning that with his invisibility gadget Paradine can spy on any war council in the world. Malone tells them to capture Paradine even though none of them know how, and orders them to head back Parsons Ridge. As the agents head back by train, British spy and former ally Colonel Sir David Edney steps out of the backroom. He knows about Paradine's scheme but England doesn't want a World War until 1914. Juanita and her brothers ride up and open fire on the train, and Jim goes to the coal car. He tells the engineer to speed up and throws wood at their pursuers, driving them back so they can escape. Jim then goes back inside and tells Edney that the attack was a personal affair and to stay out of his business. The British spy prudently rides with the engineer for the rest of the trip.
Back at Parsons Ridge, Edney's assistant Mirabelle Merriweather greets them and explains that Paradine has invited them to join him at the saloon for champagne. They go there and Edney orders Jim and Artie to place Paradine under arrest for murder. They refuse and Paradine dares Edney to arrest him, but then turns invisible and disarms him. Once he reappears, he tells them that he controls everything within a hundred miles and tells them to leave the town. Another explosion goes off and Paradine tells them that they can find him at his place in the desert if they wish to surrender. He turns invisible again and leaves, and a disgusted Edney says that he and Miranda will work on their own as they go.
Sometime later in Washington, Secretary of State Henry Messenger shows Malone Edney's letter of protest over the Paradine affair. When Malone admits that he hasn't heard back from Jim and Artie, Messenger tells him to go to Nevada and supervise personally.
Jim and Artie discover that Paradine has posted direction signs to his lair and wonder what to do since Paradine hasn't yet violated any crimes. They discover that Paradine's lair is an oasis with a large circus tent. Inside they find hundreds of gamblers and circus acts. Paradine welcomes them and explains that gamblers come from all over the world to place bets, and that his casino is on a major route to the West Coast. The agents are still at a loss for what to charge him with, and Paradine offers them some casino chips on the house and tells them to have a good time. Jim refuses but Artie is eager to try his new system.
Artie is soon winning big at the roulette table and Paradine has the wheelman close the game down. He then leads them to a private area by the animal cages and offers Artie his $15,000 in winnings as a bribe. The agents dump the chips on Paradine's head and the villain flies into a rage. He unleashes his two henchman, large green-skinned "hulks," who quickly subdue the agents.
The agents wake up and find themselves suspended upside down over a lion cage. Paradine is disappointed that they haven't provided him with a challenge and informs the agents that he's going to Washington to meet with Dr. Messenger, who is hosting an international peace conference. Paradine leaves with his hulks and the agents try to work a way out of their predicament.