Mirza won the 2003 Wimbledon Championships Girls' Doubles title, teaming up with Alisa Kleybanova of Russia.

Mirza is the highest ranked female tennis player ever from India, with a career high ranking of 27 in singles and 18 in doubles. . She holds the distinction of being the first Indian woman to be seeded in a Grand Slam tennis tournament . Earlier in 2005, she had become the first Indian woman to reach the fourth round of a Grand Slam tournament at the 2005 U.S. Open, defeating Mashona Washington, Maria Elena Camerin and Marion Bartoli. In 2004, she finished runner up at the Asian Tennis Championship.

In 2005, Mirza reached the third round of the Australian Open, losing to eventual champion Serena Williams. On February 12, 2005, she became the first Indian woman to win a WTA singles title, defeating Alyona Bondarenko of Ukraine in the Hyderabad Open Finals. As of September 2006, Mirza has notched up three top 10 wins; against Svetlana Kuznetsova, Nadia Petrova and Martina Hingis. At the 2006 Doha Asian Games, Mirza won the silver in the women's singles category and the gold in the mixed doubles partnering Leander Paes. She was also part of the Indian women's team that won the silver in the team event.

Mirza had the best results of her career during the 2007 summer hardcourt season, finishing eighth in the 2007 U.S. Open Series standings. She reached the final of the Bank of the West Classic and won the doubles event with Shahar Pe'er, and reached the quarterfinals of the Tier 1 Acura Classic.

At the 2007 U.S. Open, she reached the third round before losing to Anna Chakvetadze for the third time in recent weeks. She fared much better in the doubles, reaching the quarterfinals in mixed with her partner Mahesh Bhupathi and the quarterfinals in the women's doubles with Bethanie Mattek, including an impressive win over number two seeds Lisa Raymond and Samantha Stosur.

She represented India at the 2008 Summer Olympics in Beijing, in the women's singles and doubles events. In singles, she retired in the round of 64, while she was trailing 1-6, 1-2 against Iveta Benešová of Czech Republic. She teamed up with Sunitha Rao for the doubles event. They got a walk-over in the round of 32, but lost to Russia's Svetlana Kuznetsova and Dinara by 4-6, 4-6, in the round of 16.

Mirza received an honorary degree of Doctor of Letters from MGR Educational and Research Institute University in Chennai on 2008-12-11.