Spiro's first film role was as Catherine Reece in the 1999 film, From Dusk Till Dawn 3: The Hangman's Daughter, a direct-to-DVD prequel to the 1996 film From Dusk till Dawn.
Additional credits include The Year of Getting to Know Us which premiered at the 2008 Sundance film festival, IFC's Alone with Her, as well as guest appearances on Cold Case, Out of Practice, and CSI: NY.
Spiro also appeared in the 2009 comedy The Goods: Live Hard, Sell Hard alongside Jeremy Piven, Ed Helms and Rob Riggle, and produced by Will Ferrell and Adam McKay. The Goods was directed by Neal Brennan.
Spiro was scheduled to star in the planned 2010–11 television series Love Bites, but fell out of the role in June 2010 due to other contractual obligations. Spiro was most recently cast alongside Nicolas Cage and Nicole Kidman in the thriller, Trespass. She was a guest star on the Showtime 2011 season of Dexter. For the 2012–13 season, she had the lead role in the Fox-TV medical/crime drama The Mob Doctor.
She is married to Matthew Spitzer, and in May 2014 it was announced she was expecting their first child.
Her debut feature Night Comes On, which she directed and co-wrote (with Angelica Nwandu) premieres at the Sundance Film Festival in 2018. She developed the film at the Sundance Institute’s Directors, Screenwriters, and Composers Labs, and through a Cinereach development grant. Her short Skin premiered at Sundance and won the Women In Film Productions award. Skin also won the Honorable Mention Award at SXSW, showed at Telluride, Palm Springs, and AFI among others. Jordana earned her MFA in Film from Columbia University (2015) and received the Adrienne Shelly Foundation Fellowship. She studied drama at the Circle in the Square Theatre School in New York and was selected to join the Berlinale Talent Campus in Berlin.