With an improved ranking, Stephens was able to play WTA Tour-level events the entire season. Early in the year, she played in her first Australian Open main draw and made it to the second round. Stephens then closed out the winter hard court season by qualifying for the Miami Open. Having played there every year since 2008, she picked up her first two main draw wins at the tournament, including the second one over No. 30 Sara Errani. In late April, Stephens made her Fed Cup debut in an away playoff tie against Ukraine. She won her only match, a doubles dead rubber with partner Liezel Huber, as the United States won the tie 5–0 to return to the top-level World Group in 2013.
At the Cincinnati Open in August, Stephens scored her second big upset of the year when she knocked out Sharapova, the No. 3 player in the world, in the second round. She lost in the next round to No. 15 Jelena Jankovic. Two weeks later, Stephens entered the US Open as the 15th seed, where she faced Williams again in the fourth round. This time, Williams avenged her Australian Open loss in straight sets and went on to win the tournament. Although Stephens continued to struggle outside of the majors after the US Open, she was named the second alternate for the WTA Tour Championships. She finished the year at world No. 12 and was one of only three players to make it to the second week of all four Grand Slam tournaments in 2013, along with Williams and Agnieszka Radwańska. Stephens also reached a career-high ranking of No. 11 in October and became the second-highest ranked American.
Stephens entered the US Open at No. 83 in the world, and still needed to use a protected ranking to be accepted into the main draw due to the entry deadline being over a month before the event. Her first upset of the tournament came in the second round over No. 10 Dominika Cibulková. In the fourth round, she defeated No. 33 Julia Görges to advance to her first US Open quarterfinal and her first major quarterfinal since Wimbledon in 2013. She then defeated No. 17 Anastasija Sevastova to set up the first all-American semifinals at a major since Wimbledon in 1985, and the first at the US Open since 1981. Her semifinal was against No. 9 Venus Williams. After two lopsided split sets, Stephens won a tight third set to reach her first Grand Slam singles final. Madison Keys won the other semifinal against CoCo Vandeweghe. Stephens closed out the tournament by defeating Keys in straight sets to win her first Grand Slam tournament title. She became the first American woman other than the Williams sisters to win a major title since Jennifer Capriati won the Australian Open in 2002 and the first to win the US Open since Lindsay Davenport in 1998. She also became the lowest-ranked US Open champion ever, and the fifth-lowest at any Grand Slam tournament.
Stephens has a 1–5 record against Serena Williams, with three of their matches coming in 2013 and the other three in 2015. Her only victory against Serena came at the 2013 Australian Open when she was still relatively unknown as a 19-year-old. The match win and her run into a Grand Slam singles semifinal garnered international attention and put her on the cusp of cracking the top 10 of the WTA rankings later in the season. With Serena entering the match in excellent form and also having defeated her much younger opponent earlier that month, Stephens was listed as high as a 16-to-1 underdog. All of their matches since have been contested at high-level Premier tournaments or Grand Slam tournaments. In 2015, Stephens won the first set of their encounters at the Indian Wells Open and the French Open, but ultimately lost in three sets in both instances.