Ono first met John Lennon when he visited a preview of an exhibition of Ono's at the Indica Gallery in London on November 9, 1966. Lennon's first personal encounter with Ono involved her passing him a card that read simply "Breathe". He was taken with the positivity, humour, and interactivity of her work.
They began an affair approximately two years later, eventually resulting in Lennon divorcing his first wife, Cynthia Lennon.
Lennon referred to Ono in many of his songs. While still a Beatle he wrote "The Ballad of John and Yoko", and he alluded to her indirectly in "Julia", a song dedicated to his mother, with the lyrics: "Ocean child calls me, so I sing a song of love" (The kanji 洋子 ("Yoko") means "ocean child"). Other Lennon songs about Ono are said to include: "I Want You (She's So Heavy)", "Don't Let Me Down", "Happiness Is a Warm Gun", "Well Well Well", "Oh Yoko!", "I'm Losing You", "Bless You", and "Dear Yoko". 
Ono and Lennon collaborated on many albums, beginning in 1968 when Lennon was still a Beatle, with Unfinished Music No.1: Two Virgins, an album of experimental and difficult electronic music. That same year, the couple contributed an experimental piece to The White Album called "Revolution 9". Ono also contributed backing vocals (on "Birthday"), and one line of lead vocals (on "The Continuing Story of Bungalow Bill") to The White Album. Many of the couple's later albums were released under the name the Plastic Ono Band. The couple also appeared together at concerts; when Lennon was invited to play with Frank Zappa at the Fillmore on June 5, 1971, Ono joined in as well.
Ono and Lennon married on March 20, 1969 in Gibraltar.
Ono has been accused by some music historians, of breaking up The Beatles, while others argue that the breakup was caused by the fact that the Beatles were moving in different directions musically and personally. Lennon, also, said he had wanted to leave the group even before he met Yoko. In a 2003 interview with Jay Leno, Yoko revealed the disappointment she felt by the breakup and the impact it had on a life that she was used to.
After the Beatles disbanded, Lennon and Ono cohabitated in London and then in New York. They were arrested for possession of cannabis resin on October 18, 1968. The arrest would be significant to their future together. Their relationship was very strained as Lennon faced near-certain deportation from the United States based on the British drug charges and Ono was separated from her daughter, who would have remained behind if she followed Lennon back to England. Lennon began drinking heavily and Ono buried herself in her work. The marriage had soured by 1973 and the two began living separate lives, Ono pursuing her career in New York and Lennon living in Los Angeles with personal assistant May Pang.
In 1975, the couple reconciled. Their son, Sean, was born on Lennon's 35th birthday, October 9, 1975. After Sean's birth, the couple lived in relative seclusion at the Dakota in New York. Lennon retired from music to become a house-husband caring for their child, until shortly before his murder in December 1980, which Yoko witnessed at close range.