In April 2003, Mirza made her debut in the India Fed Cup team, winning all three singles matches. She also 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 insingles and 18 in doubles. She is the first Indian woman to be seeded in a Grand Slam tennis tournament. She was 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 winning, with Mahesh Bhupathi, the mixed doubles event at the 2009 Australian Open, she became the first Indian woman to win a Grand Slam title.