She raised her profile significantly as one of the four regulars of HBO's successful comedy Sex and the City (1998-2004), as the no-nonsense lawyer Miranda in support of series star Sarah Jessica Parker. After Emmy nominations as Outstanding Supporting Actress in a Comedy Series in 2002 and 2003, Nixon took home the trophy in 2004 for the series' final season.

The immense popularity of the series led Nixon to enjoy her first leading role in a feature, playing a video artist who falls in love, despite her best efforts to avoid commitment, with a bisexual actor who just happens to be dating a gay man (her best friend) in Advice From a Caterpillar (2000), as well as starring opposite Scott Bakula in the holiday telepic Papa's Angels (2000). In 2002 she also landed a stint as Mrs. Piggee in the indie comedy Igby Goes Down, and her turn in the theatrical production of Clare Booth Luce's play The Women was captured for PBS's Stage On Screen series.

Post-Sex, Nixon did a guest