Starting the year ranked No. 378 in the world, Duan's ranking would improve significantly to No. 128 by the year's end. Some of the highlights of her 2012 season included winning four ITF titles at the 25k level in Wellington, Changwon, Gimcheon and Goyang. Playing qualifying at the US Open, Duan had her first experience in a Grand Slam tournament. She would win her first qualifying round defeating Réka-Luca Jani, but would fall in the next round to Kirsten Flipkens. She received a wildcard to the Guangzhou International and won her first WTA main draw match defeating Luksika Khumkum in the first round. Duan also achieved her best results in ITF challengers near the end of 2012, reaching the semifinals of 100K+H Ningbo and the finals of 100K Suzhou, losing both matches to top-100 veteran Hsieh Su-wei.
Duan was due to make her main draw Grand Slam singles debut at Wimbledon, but withdrew to compete in the National Games of China. She made her Grand Slam singles debut in the main draw of the US Open after winning three qualifying matches. She lost to sixth seed Caroline Wozniacki in the opening round. During the televised commentary of her match against Caroline Wozniacki, the commentators compared Duan's game to that of former world No. 1, Lindsay Davenport. They also began referring to her by the nickname of Duan-venport (段文波特) on the Chinese internet.
As a qualifier, Duan beat 2014 finalist Eugenie Bouchard 7–6(7–3), 6–4 in the first round of Wimbledon. This match was considered as one of the biggest upset of the tournament. In the second round, Duan lost to Tatjana Maria from Germany in a long three-set match by 6–1, 2–6, 8–10.