She was a member of the Second City troupe in Toronto that would go on to create the sketch comedy series SCTV. She would have been a cast member with Saturday Night Live after NBC stepped in to retool the show following Jean Doumanian's tenure in 1981, but O'Hara decided to stay with SCTV. There is a long-standing story that controversial SNL writer Michael O'Donoghue scared O'Hara off by screaming at everyone for ruining the show and spraypainting the word, "DANGER!" all over her dressing room door, but O'Hara has gone on record and stated that she passed up being an SNL cast member because she wanted to stay loyal to SCTV, which was about to air on NBC in the early 1980s.
Since then, she has had done several movies, some of them having involvement from Tim Burton. Among her most well-known roles is playing Kate McCallister in the first two Home Alone films. She also stars as Moira Rose on CBC's Schitt's Creek, opposite long-time collaborator Eugene Levy. In 2020, O'Hara won Best Actress in a Comedy Series as part of Schitt's Creek's 2020 sweep of the Emmy Awards. She and Levy previously won in 1983 for writing SCTV.
Her husband, Bo Welch, is a production designer.
Film and TV appearances:
- A Mighty Wind — Mickey Crabbe
- A Series of Unfortunate Events (2004) — Justice Strauss
- A Series of Unfortunate Events (2017) — Dr. Georgina Orwell
- Barbie in the Twelve Dancing Princesses - Duchess Rowena
- Beetlejuice — Delia Deetz
- Frankenweenie — Mrs. Susan Frankenstein / "Weird Girl," / Gym Teacher
- Home Alone — Kate McCallister
- Home Alone 2 — Kate McCallister
- Orange County — Cindy
- Schitt's Creek — Moira Rose
- Skylanders Academy — Kaossandra
- The Nightmare Before Christmas — Sally / Shock
- Over the Hedge — Penny
- Sofia the First — Morgana
- When Marnie Was There — Elderly Lady
- Wyatt Earp — Allie Earp
- Actor-Inspired Element: Suggested Moira Rose's fashion be inspired by Daphne Guinness and suggested that Moira wear wigs to suit her mood and have an unrecognizable accent.
- The Alcoholic: Is excellent at playing intoxicated characters.
- The Cast Show Off: Often is cast in roles where she is required to sing and show off her vocal talents.
- Harpo Does Something Funny: The dialogue on Schitt's Creek is tightly scripted, but O'Hara arranges the music for Moira's performances.
- Improv: Started at Second City, and shes appeared in the Christopher Guest directed mockmentaries that are largely improvised.
- Irony as She Is Cast: Often plays mediocre singers and actors, when she herself is very talented at both.
- Production Posse: Alongside Eugene Levy, she is part of Christopher Guest's ensemble. Also often works with Tim Burton's ensemble.
- Those Two Actors: With Eugene Levy, whom she has played opposite in many projects over the decades.