Adapted from a novel by Larry Evans, Once to Every Man tells the tales of Danny Bolton, a pugnacious, hard-drinking country boy.

The son of an American mine owner, traveling under the name of Charles Conant, tries to enter England in 1916 after masquerading as a muleteer, but the captain of his ship, suspicious when he sees Charles look through a spyglass, plans to take him back to the United States. Charles escapes and visits his relative, Lady Dartridge, where he falls in love with her daughter, Lady Joan Templar, who is loved by her cousin, the chief constable, George Templar. Templar, suspicious of Charles' manner and unexplainable meetings and activities, wants to arrest him as a spy.

Convent raised Doris Elliott moves to New York to live with her brother Richard not knowing that he is part of a drug trafficking ring controlled by unscrupulous ward boss Michael O'Leary. At first Doris remains ignorant of the pervasiveness of crime and corruption in the Lower East Side until her friend, Mamie Bronson, whose brother, "Dopey Benny," has fallen victim to drugs, confesses that O'Leary has raped her. When O'Leary breaks into their home and attempts to rape her as well, he is shot when Richard unexpectedly arrives. Finding O'Leary dead and Richard unconscious, the police arrest Doris, and she is tried for murder. Defense lawyer Thomas McDonald, who has been working to expose the politician, is losing his case when Dopey Benny testifies that he killed O'Leary to avenge his sister's assault. Acquitted Doris is now free to marry Thomas.

Chorus girl Peggy Malone marries press agent Jimmy Parsons but faces hardship when her shiftless family moves in, causing Jimmy to fall ill and go West for health. Peggy follows, becomes a film star, and ultimately chooses the now-successful Jimmy over a wealthy suitor, securing their future together.

A wealthy young athlete comes to the aid of a beautiful heiress, whose fortune is being threatened by two arch villains, The Great Master and Doctor Zulph.

"Basher Bill," a retired prizefighter turned criminal, pretends to reform by joining a Salvation Army shelter in London run by a pious wraith named Elizabeth. Attracted to Elizabeth (although he is engaged to a street girl named Annie), Bill confesses to a bank robbery, has a spiritual revelation, and decides to go straight. His cast-off sweetheart reports him to the police; then, contrite, she warns Bill of the impending danger. Bill is captured immediately, but he escapes and sacrifices his life to save Elizabeth and the Salvation Army nursery when the rest of the gang use them as a human barricade against the police.

"In the Gay Nineties New York had grown up into bustles and balloon Sleeves ... but The Bowery had grown younger, louder and more rowdy until it was known as the 'Livest Mile on the face of the globe' ... the cradle of men who were later to be famous.

When her two roommates, Maude Raynes and Helen Bartlett, become engaged, Darcy Cole invents a titled fiancé of her own, in part to ward off her friends' nasty remarks about her untidy appearance.

While traveling on her honeymoon, newlywed Milly Morehouse overhears her husband Bob boast to his friend Dick Elliot that she was "easy to get," so Milly decides to get even.