She practiced fencing in high school, and ranked 3rd in a tournament in Tokyo in 1991.
She began her career as a model in commercials, notably for the confectionery company Lotte (ロッテ), then debuted in acting in 1992 in the dramaSono Toki, Heart wa Nusumareta. She became a swimsuit model for the swimwear company Unitika in 1993, and got popular as an idol, partly due to her then unusual tomboyish look with short hair and husky voice. She began to get large exposure in commercials and media, and hosted her own weekly 30mn late radio show, Yozora ni YOUKISS!, from April 1994 to March 2001 on Nippon Broadcasting.
She released her first single at the end of 1994, "TENCA wo Torou!", theme of one of her dramas, which ranked number 1 at oricon music charts, the first time for a solo debuting female singer, with a record of sales in this category only topped by Erika Sawajiri's debut single 12 years later. She went on a successful singing career for the next two years, her first album ranking number 1, with hits written by Tetsuya Komuro (notably "Only You" and "Baby's Growing Up"), a career which she stopped in 2000 to concentrate on acting.
She was cast in many dramas and movies, often as the lead actress, most notably in the live movies adaptations of the famous mangaHana yori dango (Boys over Flowers) (as Makino) in 1995, and Cat's Eye (as Ai) in 1997. She retired from show-business when she married actor Hidetaka Yoshioka on November 28, 2002, but returned to acting in 2006, after her divorce in December 2005. After 10 years away from the big screen, she made her come back to cinema in 2007, in Takeshi Kitano's "Kantoku Banzai!", and in the leading role of "Welcome to the Quiet Room", movie set in a psychiatric hospital, in which she appears in all the scenes. From 2012 until 2017, she has played anesthesiologist Hiromi Jonouchi in the popular medical drama, Doctor-X Surgeon Michiko Daimon.
Incidentally, popular actor Shun Oguri, big fan of Yuki Uchida, stated that he unintentionally started his career by joining Uchida's acting school in the 90s with the only hope of meeting her. He played Rui Hanazawa, Tsukushi Makino's first love, in the Japanese drama "Hana Yori Dango" ten years after she played Makino in the film.