After a failed attempt at breaking through on US television with a recurring role on the quickly cancelled sitcom "If Not For You" (CBS, 1995), Oh won the part of Rita an overworked and underpaid assistant to tactless sports agent Arliss Michaels (Robert Wulh) in the HBO comedy "Arli$$" (1996-2002). She was awarded a 1997 Cable ACE Award for her performance, and proved her comic capabilities while exposing her talents to an American audience. The abbreviated "Arli$$" seasons (only 13 episodes per year) gave Oh an opportunity to remain active in features, and the actress gave a memorable turn as a stereotypical Los Angeles publicist in 1997's "Bean" and appeared in the fact-based drama "Permanent Midnight" (1998) before taking a leading role in Canadian actor-director-writer Don McKellar's acclaimed Armageddon-themed feature "Last Night" (1998). The thoughtful and straightforward film, which follows several Torontonians' last few hours on earth before a mysterious but pre-warned apocalyptic event, paired Oh with McKellar as two lost souls who see life out together. She played a woman whose car is vandalized in the rioting surrounding the final day and is unable to get home or to reach her husband (David Cronenberg), with whom she had planned to commit suicide in the last moments rather than be killed by whatever force was taking life on Earth away. She then meets up with McKellar's Patrick Wheeler, a man more than happy to spend his last hours alone. Oh's performance in this quietly fascinating feature was impressive and unsettling while remaining highly watchable. "Last Night" also starred Callum Keith Rennie, who played Oh's love interest in "Double Happiness,” and not surprisingly earned the actress her second Genie. She was featured the following year in the Canadian films "The Five Senses" and Francois Girard's "The Red Violin” The latter, an epic tale co-scripted by McKellar spanning centuries and following the travels of the titular instrument was a festival favorite. Later that year she was featured in Audrey Wells' "Guinevere", playing a previous protégée of Connie (Stephen Rea), an artist and procurer of young women. Also in 1999, Oh had a two-episode stint as a no-nonsense faculty member on The WB's high school teen drama "Popular.”

She had one of her best roles playing a romantically challenged exotic dancer in Michael Radford's Los Angeles strip club-set "Dancing at the Blue Iguana" (2000), a feature also starring Jennifer Tilly and Daryl Hannah; played a school principal in Garry Marshall's teen Cinderella fantasy "The Princess Diaries" (2001), had a significant role as Bambi Kanetaka in the ensemble cast of Showtime's Armistead Maupin's Further Tales of the City" (2001),had a recurring role on the family legal drama "Judging Amy" as police detective Shelly Tranin 2001, appeared in a supporting turn in the Frankie Muniz kid revenge comedy "Big Fat Liar" (2002) and cameoed in director Steven Soderbergh's A-list indie effort "Full Frontal" (2002). Her highest profile file role at that point was as Patti, one of Diane Lane's sympathetic gal pals who sends her on a trip to Tuscany to shake off her romantic malaise in the romantic comedy "Under the Tuscan Sun" (2003), but her career got a major boost in 2004 when she appeared in the serio-comic "Sideways" as a winery employee who become romantically entangled with a libidinous bridegroom (Thomas Hayden Church) on a pre-wedding road trip. The film was written and directed by Oh's husband, Alexander Payne, and resulted in much critical acclaim for the actress – however, Payne and Oh announced their split shortly after the 2005 awards season.

The actress remained highly visible with her role as the emotionally-bottled and manipulative physician Cristina Yangon the ABC medical drama "Grey's Anatomy" (2005- ) who strikes up a complicated interracial romance with a cocky surgeon (Isaiah Washington). She won a Golden Globe award for Best Performance by an Actress in a Supporting Role in a Series, Mini-Series or Motion Picture Made for Television, as well as a Screen Actors Guild Award for Outstanding Performance by a Female Actor in a Comedy Series. Meanwhile, she earned an Emmy award nomination for Outstanding Supporting Actress in a Drama Series in 2005, an accomplishment she repeated in 2006 and 2007.

In addition to her film and television work, Oh has accumulated a number of theater credits, beginning her stage work in community productions at age ten. After completing high school, Oh left her home in the Ottawa suburb Nepean for Montreal to train at National Theatre School of Canada. She went on to take strange roles including that of a chubby young boy (odd for a thin grown woman) in Peter Hinton's "The Witch of Edmonton" before a notable turn in David Mamet's difficult "Oleanna" at London, Ontario's Grand Theatre. The following year she gave a memorable performance in "Inquest,” convincingly playing a police officer in this fact-based tale of the murder of an indigenous Canadian man. In 1998 she was featured in San Diego's La Jolla Playhouse production "Dogeaters" and also starred in the New York stage production "Stop Kiss,” earning a Theater World Award for her performance as a sexually conflicted young woman who is the target of a vicious hate crime. In 2002 Oh played Adela in "The House of Bernarda Alba" play by Federico Garcia Lorca, adapted by Chay Yew at the Mark Taper Forum in Los Angeles.