Miner's television credits include Vickie in Shining Time Station: 'Tis a Gift (1990), Michelle Bauer on Guiding Light (1989–1995), a guest starring role as Laurel in a Sex and the City episode, "Twenty-something Girls vs. Thirty-something Women" and Astrid in NY-LON.

In 2001, she starred in Bully. The plot follows several young adults in South Florida who enact a murder plot against a mutual friend who has emotionally, physically and sexually abused them for years. The film itself was based on the July 15, 1993 murder of Bobby Kent. Bully received mixed reviews from critics and has a "Rotten" rating of 54% on Rotten Tomatoes based on 91 reviews with an average score of 5.7 out of 10. The film holds a score of 45 out of 100 on Metacritic, based on 26 critics indicating 'Mixed or average reviews'. Miner won an award at the Stockholm Film Festival for Best Actress.

Among her theater credits are as "Jennifer" in Laura Cahill's Naked Faith: The Way at Naked Angels in New York (1994), Margot Frank (replacing original cast member Missy Yager) in The Diary of Anne Frank on Broadway (1997), Rivkele in Donald Margulies's adaptation of Sholem Asch's God of Vengeance at ACT Theatre in Seattle (2000), Sandy in Rebecca Gilman's Blue Surge at the Goodman Theatre in Chicago (2001) and at The Public Theater in New York (2002).

A third-generation actor, Miner is the daughter of Director and Teacher Peter Miner and the granddaughter of director/producer Worthington Miner and Actress Frances Fuller. In 1998, she married Home Alone actor Macaulay Culkin. The couple separated in 2000 and divorced in 2002.

In 2005, Miner portrayed a young woman on a journey to discover who she is and why multiple enemies want her dead in the action film Circadian Rhythm. The movie was critically ignored, and was poorly received in its few reviews. One reviewer stated that the film was a "directionless jumble of boring scenes strung together tenuously by a plot that feels like they were making it up as they went along," and that watching the film's allegedly ‘wire-fu’ fight scenes was akin to "being over at a friend's house when they’re getting yelled at by their parents."

From 2009-13, Miner took over the role of Meg Masters, a recurring antagonist and demon in Supernatural. The Writers wanted Meg's original Actress Nicki Aycox to reprise the role in later seasons, but ultimately cast Miner for storyline purposes. The character was eventually killed off later. Tim Janson of Mania gave Miner's portrayal of Meg a positive review, saying no one played Meg "with such dripping sarcasm as Rachel Miner". He felt she "always adds spice when she appears". Similarly, Diana Steenbergen of IGN felt Miner played the role "with vicious flair" and "[conveyed] Meg's brutality well, right from the beginning". As time passed, she noted that the Actress "has done well taking over the role".

Miner was diagnosed with Multiple sclerosis in 2010.