She is known for her roles as Karen Arnold, Kevin Arnold's rebellious teenaged hippie sister in the ABC comedy-drama series The Wonder Years (1988–1993), as female serial killer Nicole Wallace in Law & Order: Criminal Intent, as Marie Blake on The Single Guy (1995–1997), and Jane Porter in The Legend of Tarzan (2001–2003).

D’Abo played a lesbian visiting college professor/writer named Perry Marks, who became friends with Julia Salinger, for 3 episodes in season 5 (1999) of Party of Five.

[5] D'Abo made five appearances as a recurring villain Nicole Wallace in the NBC police procedural drama series Law & Order: Criminal Intent between 2002 and 2008.

She has had numerous supporting roles in other television series and films including The Spirit of '76 (1990), Greedy (1994), The Big Green (1995), and The Twilight Zone (2002).

Onstage, she appeared in the 2005 Broadway theatrical production of The Odd Couple alongside Matthew Broderick and Nathan Lane.

In animation, d'Abo provided the voices of Sonya Blade in Mortal Kombat: Defenders of the Realm (1996); Melanie Walker/Ten in Batman Beyond (1999–2000); Star Sapphire in Justice League (2001); and Morgaine le Fey in Justice League Unlimited (2004); Tak in Invader Zim (2001–2002); Jane Porter in The Legend of Tarzan; Jedi Master Luminara Unduli in Star Wars: The Clone Wars (2008), which she reprised the character in the cameo role in Star Wars: The Rise of Skywalker (2019); Carol Ferris in Green Lantern: First Flight (2009); and Natalia Romanoff in Ultimate Avengers and Ultimate Avengers 2: Rise of the Panther (both 2006).

In February 2013, d'Abo began filming for Tesla Effect: A Tex Murphy Adventure (working title: Project Fedora), a video game that combined live-action footage with 3D graphics.