Serena Williams defeated Victoria Azarenka in the final, 6–2, 2–6, 7–5 to win the women's singles tennis title at the 2012 US Open. Azarenka served for the championship and led 5–3 in the third set. It was the first time since 1995 that the final went to three sets. With the victory, Williams became the third woman in history to win Wimbledon, the Olympics, and the US Open in the same season after Steffi Graf and her sister Venus Williams. Williams lost only one set during the tournament, to Azarenka in the final.
Samantha Stosur was the defending champion, but she was defeated in the quarterfinals by Azarenka.
Three-time US Open champion Kim Clijsters, who was on a 22-match winning streak at the tournament, lost to Laura Robson in the second round, her earliest exit at the tournament since 2000 and her first defeat since losing to Justine Henin in the 2003 final. This was also Clijster's last tournament before her second retirement (her first being in 2007), until she returned to the tour in 2020 at the Dubai Tennis Championships.
This tournament was the first major main draw appearance for future two-time Grand Slam champion and world No. 1Garbiñe Muguruza, who lost to Sara Errani in the first round. It was also the first major main draw appearance for future WTA Finals champion Elina Svitolina, who lost to Ana Ivanovic in the first round. This also marked the first time Ivanovic had reached the quarterfinals of a major since winning the 2008 French Open.