Chen narrowly defeated the Kuomintang candidate Huang Jun-ying with a margin of just 1,120 votes in the 2006 Kaohsiung mayoral election. After announcement of the election result, Huang filed two lawsuits against Chen's campaign team, requesting the court to annul the election. He argued airing of a video, produced by Chen's campaign team, on the eve of the election resulted in his loss. The Kaohsiung District Court ruled in favor of Huang in one of the lawsuits, thus nullifying the election. Chen expressed her intention to appeal to the court upon knowing the verdict. She claimed it would be a political suicide if she accepted the ruling. While her colleague and Democratic Progressive Party legislator Kuan Bi-ling advised Chen to concede, Chen nonetheless appealed the ruling. There were speculations on whether Kuan, who lost to Chen during the primaries, made the remark out of personal interest. The High Court eventually overturned the earlier decision of the Kaohsiung District Court and revalidated the election result on 17 November 2007. Chen announced, after all legal proceedings against the mayoral election result had ended, that her policy priorities would be the city's transportation, infrastructure construction and environmental protection.
Chen assured the public in April 2009 she would improve the water quality of Chienchen River, nicknamed "Heilungchiang" by the locals for its apparent pollution. She pledged NT$120 million to implement the water treatment project. Chen vowed to make Kaohsiung a city not just notable for the beauty of the Love River.
Kaohsiung was the host city of 2009 World Games. Chen visited China in that year to promote the Games and met with then-Mayor of Beijing Guo Jinlong. Chen addressed then-President Ma Ying-jeou with his formal title during the meeting with Guo, which garnered much support from her party and the Kaohsiung City Council. However, she was criticized by several Taiwanese localist groups, including the Taiwan Solidarity Union. In response, Chen said the trip was meant to be beneficial to Kaohsiung. In addition to Guo, she also met with then-Mayor of Shanghai Han Zheng and former Chinese Olympic Committee chairman Liu Pong during her trip to China. Main venue of the Games, the World Games Stadium, was designed by Japanese architect Toyo Ito. Both the groundbreaking and completion of the Stadium occurred during Chen's tenure of mayorship. The closing ceremony was held in the sold-out World Games Stadium, where President of the International World Games Association Ron Froehlich called the Games a "fantastic success" and declared it "the best ever". Tourism Bureau of Kaohsiung announced the Games generated nearly US$61 million in revenue for the city. The city's department stores reported a 15-percent growth in sales. Chen said Kaohsiung would no longer be known only as the second largest city in Taiwan, but also the one that hosted the best World Games ever.
Chen was criticized for having a nap in her residence while many parts of Kaohsiung were flooded during Typhoon Fanapi on 19 September 2010. Chen tearfully apologized, saying she felt guilty for taking a rest. Stressing that she returned her residence to change her wet clothes, Chen indicated she was also keeping a close eye on the rainstorm. Critics called for her immediate resignation and compared Chen's behaviour to then-Premier Liu Chao-shiuan's haircut and then-Secretary-General of the Executive Yuan Hsieh Hsiang-chuan's attendance at a Father's Day dinner during Typhoon Morakot in August 2009. Chen and the Kaohsiung City Government were sued by Lin Chi-mei, a fellow party member and local official from Benhe Village, in the aftermath of the flooding. She alleged the local government did not maintain properly the flood control facilities.
Kaohsiung residents criticized Chen for taking an apathetic attitude in the 2014 Kaohsiung gas explosions. The Kuomintang caucus in the Kaohsiung City Council sued her for negligence which led to casualties. A subpoena was issued to Chen and three other municipal officials on 22 September 2014. The Kaohsiung District Prosecutors' Office decided on 18 December 2014 not to indict Chen.
2014 Kaohsiung mayoral election
Chen launched her second reelection campaign in 2014 and defeated the Kuomintang candidate Yang Chiu-hsing in the mayoral election, held on 29 November 2014, with 68.09% of the votes.