Watkins debuted in 1989 as the fiddler of Nickel Creek, the progressive bluegrass group she formed with her brother Sean and mandolinist Chris Thile.

[3] In late 2005, Watkins stated in a PopMatters interview when discussing her first solo-written recorded song, "Anthony", that she "definitely [makes] the effort [to write more], but it's something that doesn't come too easy for me.

On April 14, 2009, she appeared on Late Night with Jimmy Fallon, with Jones on bass, Questlove of The Roots on drums, and her brother Sean Watkins on guitar.

[10] Produced by former Simon Dawes guitarist Blake Mills, it features guest appearances from Fiona Apple and Jackson Browne.

In 2002, Watkins starred in an advertisement for cell phone provider Cingular Wireless alongside her former fiddle teacher Dennis Caplinger, as well as other prominent bluegrass artists.

[11][12] Between 2000 and 2004, Watkins and the other members of Nickel Creek (Chris Thile and Sean Watkins), Glen Phillips, John Paul Jones, and Pete Thomas collaborated on an EP, Mutual Admiration Society Solo Sampler; an album, Mutual Admiration Society (recorded in 2000); and a brief tour.

In June 2010, Watkins appeared on the Nerdist podcast as a musical guest, performing her best-known solo song, "Long Hot Summer Days" (a John Hartford cover).

Watkins played violin and sang on "A Face To Call Home" on John Mayer's 2012 album Born and Raised.

Keyboardist Benmont Tench (of Tom Petty and the Heartbreakers) and bassist Sebastian Steinberg (formerly of Soul Coughing) are regular participants, and other guest musicians from the Largo family generally show up as well, including Jon Brion, Fiona Apple, Don Heffington, Greg Leisz, and former Nickel Creek bandmate Chris Thile when he is in town.