While they were collaborating together in the Tourists, Lennox and Stewart became lovers. Soon, tensions within the band grew and by 1980, the pair had left the band to begin Eurythmics. During the early '80s, the sleek synth pop of Eurythmics became one of the most popular sounds of new wave, racking up a number of hits in both the U.S. and U.K., including "Sweet Dreams (Are Made of This)," "Love Is a Stranger," "Who's That Girl," and "Here Comes the Rain Again." Midway through their career, Eurythmics began pursuing a harder, more straightforward rock & roll sound.

In 1990, following the release of Eurythmics' commercial disappointment We Too Are One, Lennox announced that she was taking a two-year sabbatical to have a child. During this time, the group quietly dissolved, Lennox had a baby, and she began working on her first solo album. Diva, her solo debut, arrived in 1992 and showcased a calmer, more mature vocalist designed to cross over into the adult contemporary audience. On the strength of the singles "Walking on Broken Glass" (number 14) and "Why" (number 34), Diva sold over two million copies in the U.S. alone; the album was also nominated for three Grammy awards.

Annie Lennox delivered her second solo album, a covers collection entitled Medusa, in 1995. Peaking at number 11, Medusa spawned the hit single "No More I Love You's," and went platinum by the end of 1995.