Lennon first met Yoko Ono on 9 November 1966 at the Indica Gallery in London, where Ono was preparing her conceptual art exhibit. They were introduced by gallery owner John Dunbar. Lennon was intrigued by Ono's "Hammer A Nail": patrons hammered a nail into a wooden board, creating the art piece. Although the exhibition had not yet begun, Lennon wanted to hammer a nail into the clean board, but Ono stopped him. Dunbar asked her, "Don't you know who this is? He's a millionaire! He might buy it." According to Lennon's recollection in 1980, Ono had not heard of the Beatles, but she relented on condition that Lennon pay her five shillings, to which Lennon said he replied, "I'll give you an imaginary five shillings and hammer an imaginary nail in." Ono subsequently related that Lennon had taken a bite out of the apple on display in her work Apple, much to her fury.

Ono began to telephone and visit Lennon at his home. When Cynthia asked him for an explanation, Lennon explained that Ono was only trying to obtain money for her "avant-garde bullshit". While his wife was on holiday in Greece in May 1968, Lennon invited Ono to visit. They spent the night recording what would become the Two Virgins album, after which, he said, they "made love at dawn". When Lennon's wife returned home she found Ono wearing her bathrobe and drinking tea with Lennon who simply said, "Oh, hi." Ono became pregnant in 1968 and miscarried a male child on 21 November 1968, a few weeks after Lennon's divorce from Cynthia was granted.

Two years before the Beatles disbanded, Lennon and Ono began public protests against the Vietnam War. They were married in Gibraltar on 20 March 1969, and spent their honeymoon at the Hilton Amsterdam, campaigning with a week-long Bed-In for Peace. They planned another Bed-In in the United States, but were denied entry, so held one instead at the Queen Elizabeth Hotel in Montreal, where they recorded "Give Peace a Chance". They often combined advocacy with performance art, as in their "Bagism", first introduced during a Vienna press conference. Lennon detailed this period in the Beatles song "The Ballad of John and Yoko". Lennon changed his name by deed poll on 22 April 1969, adding "Ono" as a middle name. The brief ceremony took place on the roof of the Apple Corps building, where the Beatles had performed their rooftop concert three months earlier. Although he used the name John Ono Lennon thereafter, some official documents referred to him as John Winston Ono Lennon. The couple settled at Tittenhurst Park at Sunninghill in Berkshire. After Ono was injured in a car accident, Lennon arranged for a king-size bed to be brought to the recording studio as he worked on the Beatles' album, Abbey Road.

Ono and Lennon moved to New York, to a flat on Bank Street, Greenwich Village. Looking for somewhere with better security, they relocated in 1973 to the more secure Dakota overlooking Central Park at 1 West 72nd Street.