Wells used singing as her comfort from her pain and by age ten had graduated from church choirs to performing at local nightclubs in the Detroit area. Wells graduated from Detroit's Northwestern High School at the age of 17 and set on sights of becoming a scientist but already hearing about the success of Detroit musicians such as Jackie Wilson and The Miracles decided to try her hand at music as a singer-songwriter.
In 1960, Wells approached Tamla Records founder Berry Gordy at Detroit's Twenty Grand club with a song she had intended for Jackie Wilson to record, since Wells knew of Gordy's collaboration with Wilson. However, a tired Gordy insisted Wells to sing the song in front of him. Impressed, Gordy had Wells enter Detroit's United Sound Studios to record the single, titled "Bye Bye Baby". After a reported twenty-two takes, Gordy signed Wells to the Motown subsidiary of his expanding record label and released the song as a single in late 1960 where it eventually peaked at number-eight on the R&B chart in 1961 later crossing over to the top fifty on the pop singles chart where it peaked at number forty-five.
Wells' early Motown career insisted on a rougher R&B production that predated her more smoother sound of her bigger hit recordings. Wells became the first Motown female artist to have a top forty pop single after the Mickey Stevenson-penned doo-wop single, "I Don't Want to Take a Chance", hit number thirty-three. In the fall of 1961, Motown issued her first album and released a third single, the blues-styled ballad "Strange Love". However when that record bombed, Gordy set Wells up with The Miracles' lead singer Smokey Robinson. Though she was hailed as "the first lady of Motown", Wells was technically Motown's second female signed act: Detroit blues-gospel singer Mabel John signed to the then-fledging label a year prior to Wells' arrival. However, Wells' early hits did make her the label's first female star and its first fully successful solo artist.
Wells' teaming with Robinson began a succession of hit singles the duo would collaborate on in the following two years. Their first collaboration, 1962's "The One Who Really Loves You", was Wells' first smash hit, peaking at number-two on the R&B chart and number-eight on the Hot 100. The song featured a calypso-styled soul sound that would define Wells' early hits. Later famous for releasing songs with a repetitive sound, Motown later released the similar-sounding "You Beat Me to the Punch", which became her first R&B number-one single and peaked at number nine on the pop chart. The success of "You Beat Me to the Punch" helped to make Wells the first Motown star to be nominated for a Grammy Award as the song was nominated in the Best Rhythm & Blues Recording category.
Then in late 1962, Motown released "Two Lovers". The single became Wells' third consecutive single to hit the top ten of Billboard's Hot 100 where it peaked at number-seven and became her second number-one hit on the R&B chart. This help to make Wells the first female solo artist to release three consecutive top ten singles on the pop chart. Wells' second album, also titled The One Who Really Loves You, was released in 1962 and peaked at number-eight on the pop albums chart, making the teenage singer a breakthrough star and gave her clout in the Motown label. Wells' success in Motown was recognized when she became a headliner during the first string of Motortown Revue concerts, starting in the fall of 1962. The singer showcased a rawer stage presence that contrasted from her more softer R&B recordings.
Wells' success continued in 1963 where she hit the top twenty with the doo-wop ballad "Laughing Boy" and scored three top forty singles that year including "Your Old Standby", "You Lost the Sweetest Boy", and "What's So Easy for Two Is So Hard for One". The latter song's a-side, "You Lost the Sweetest Boy", was one of the first hit singles composed by the successful Motown songwriting and producing trio Holland-Dozier-Holland though Robinson remained Wells' primary producer.
During that year, Wells recorded a session of successful b-sides that became as known as her hits including "Operator", "What Love Has Joined Together", "Two Wrongs Don't Make a Right" and "Old Love (Let's Try It Again)". Wells and Robinson also recorded a duet together titled "I Want You 'Round", the duet would be re-recorded by Marvin Gaye and Kim Weston.
 1964: Brief superstardom In 1964, Wells recorded and released her landmark single, "My Guy". The song became her landmark single reaching number-one on the Cashbox R&B chart for seven weeks becoming the number-one R&B single of the year and the song successfully crossed over to the Billboard Hot 100 where it eventually replaced Louis Armstrong's "Hello Dolly!" to hit number-one on that chart where it stayed for two weeks. To build on the song's building success, Motown released a duet album Wells recorded with fellow Motown singing star Marvin Gaye on the album, Together. The album peaked at number-one on the R&B albums chart and hit number forty-two on the pop albums chart and yielded the double-sided hits "Once Upon a Time" and "What's the Matter With You Baby".
"My Guy" was one of the first Motown songs to break over the other side of the Atlantic where it eventually peaked at number-five on the UK chart making Wells an international star that year. Around this time, despite competition, The Beatles publicly stated that Wells was their favorite American singer and soon she was giving an invitation to open for the group during their tour of the United Kingdom thus making Wells the first Motown star to perform in the UK. Wells was only one of three female singers - Brenda Holloway and Jackie DeShannon being the others - to open for The Beatles. Wells gained friendships with all four Beatles members and later released a tribute album, Love Songs to the Beatles in mid-decade.