Santa Maria was born and raised in Plano, Texas, the younger of two daughters. Her parents, a school teacher and an engineer, both came from Catholic families and converted to Mormonism together as adults, raising their children in the religion, and for a while she attended church daily before classes. Years after her parents divorced, Santa Maria left the LDS church at 15 and came out as an atheist. Through her father's remarriage, she has adoptive twin stepsisters, in addition to three half-brothers, who were also adopted. Her ancestry is English, Puerto Rican and Italian. Santa Maria worked various jobs as a teenager, including being employed at a head shop, a bakery, CiCi's Pizza, as well as in retail. In her youth, she was also involved in gymnastics.
In 2001, Santa Maria graduated from Plano East Senior High School having accumulated a year of college credit. During her high school career, she was involved in choir where she was a member of the group Sound Invention, as well as cheerleading, being promoted to captain by her teammates during one season. In addition, she qualified as an International Baccalaureate student and participated in academic competitions. Santa Maria originally entered college with the intention of studying vocal performance and jazz studies; she auditioned for the second season of American Idol but ultimately did not receive a ticket to Hollywood. She earned a Bachelor of Science degree in psychology with a minor in philosophy from the University of North Texas in 2004, before graduating with her Master of Science in biological science with a concentration in neuroscience from her alma mater in 2007. There, she also taught biology laboratory courses and performed neuronal cell culture duties and electrophysiology research at the Center for Network Neuroscience. Santa Maria then enrolled in a doctoral program studying clinical neuropsychology at Queens College, City University of New York, where she worked as an adjunct professor and laboratory researcher, but withdrew after a year of coursework to pursue science communication full-time.
Santa Maria received the Texas Psychological Association and Texas Psychology Foundation's Alexander Psychobiology/Psychophysiology Award for her contributions in undergraduate research concerning neuropsychological deficits among individuals with alcohol dependence or abuse in a visually impaired/blind population. In the clinical neuropsychological setting, she assisted in development and research of computer adapted guides for educational management of students with both neuropsychological dysfunction and visual impairment.
In 2009, Santa Maria moved to the Los Angeles area to begin a career in science communication, after previously having worked in academia. She co-produced and hosted a pilot entitled Talk Nerdy to Me for HBO, but it never went to air. Santa Maria has appeared on various programs including Larry King Live, Geraldo at Large, Parker Spitzer, Studio 11, The Young Turks, Attack of the Show!, The War Room with Jennifer Granholm, LatiNation, The Nerdist, and SoCal Connected.
Santa Maria has co-hosted Hacking the Planet and The Truth About Twisters on The Weather Channel, as well as TechKnow on Al Jazeera America. She is a former host of Take Part Live on the Pivot (TV channel).
She makes regular appearances on popular YouTube programs, such as Stan Lee's FanWars, Wil Wheaton's Tabletop, and The Point. She has also guested on multiple podcasts, such as The Nerdist Podcast, Point of Inquiry, Star Talk and the Joe Rogan Experience. Speaking with Chris Mooney on Point of Inquiry in 2012, Santa Maria recognized that her work on behalf of science can sometimes be polarizing, and said that she tries “to write with a lot of respect and reverence for people’s ideas.”
Santa Maria has been interviewed by Scientific American, The Times of London, Columbia Journalism Review, and Glamour.
In March 2014, Santa Maria debuted her weekly podcast entitled Talk Nerdy. New episodes premiere every Monday and guests typically revolve around those involved in STEM fields, however individuals with careers oriented in new media and pop culture also make appearances. Additionally, atheism and politics are popular topics of conversation.
Santa Maria wrote the foreword of atheism activist David Silverman's book, Fighting God: An Atheist Manifesto for a Religious World, published in December 2015.
On July 18, 2015, during the live taping of episode 524 of The Skeptics' Guide to the Universe podcast at The Amaz!ng Meeting, it was announced that Santa Maria would be joining the podcast, and she recorded her first show as a permanent member of the panel.
In July 2015, Santa Maria was named a correspondent on "Real Future" for Fusion.
In 2016, she hosted on-line video segments that accompany the reality TV show America's Greatest Makers.
From 2009 to 2011, Cara Santa Maria was in a relationship with television host and political commentator Bill Maher.
She has been open about her struggles with major depressive disorder. In a Point of Inquiry podcast interview, Santa Maria said that she takes antidepressants daily and that psychotherapy made a huge improvement in her mental health.