Set in the Harlem in the early 20th century, Home to Harlem tells of Jake Brown, a handsome black man and soldier in World War I. When he arrives to his theater of war, he is treated like a slave, not like a soldier, and so he defects to France.
He starts back to home in Harlem as a cook aboard a vessel traveling to London, where he waits for the war to end. He finds himself a girlfriend and an apartment in England, but when he gets the opportunity to go back to the states, he takes it.
Back in Harlem, Jake bumps into Zeddy Plummer, his buddy from the war. One night, Jake falls in love with a prostitute, but he loses her apartment and can't find her after their first rendezvous. He decides that perhaps Harlem isn't the right place for him anymore, and he leaves, again by cooking, this time for a Pennsylvania Railroad train.
Jake meets Ray, a waiter on the same train. Ray is a Haitian exile and is severe and thoughtful. When Ray overdoses on drugs, Jake nurses him to health. Later, Jake becomes ill and goes back to Harlem to get treatment. It seems he hasn't been able to stay away for long. Ray takes a job as a freighter and leaves.
Finally, Jake runs back into his lover from that night so long ago. Her name is Felice. While they're celebrating their reunion (she missed him as well, it seems), Jake's war buddy Zeddy confronts him. Felice has been something like a girlfriend for Zeddy. Jake doesn't give up easily though, and he even pulls a gun on Zeddy, who retorts that Jake is a deserter and a traitor. Jake and Felice, now certain the authorities will learn of Jake's desertion, escape for a fresh start in Chicago.