Downey was born and raised in Derry, County Londonderry, Northern Ireland, in 1960, in the Bogside district. Roma is named after her two grandmothers, Ro from Rose and Ma from Mary, joined together to make Roma. She attended Thornhill College, a Catholic girls school. Her mother, Maureen O'Reilly Downey, a homemaker with an interest in the performing arts, died from a heart attack at age 48 when Downey was 10 years old. Her father, Patrick Downey, was a school Teacher by training but worked as a mortgage broker. Her father died when Downey was 20. Originally, she planned to be a Painter and earned a Bachelor of Arts at Brighton College of Art. Roma studied BA(Hons) Expressive Arts at Brighton Polytechnic (which later became Brighton University). Based at the Falmer campus Downey combined Art and Drama for her degree. However, she turned her attention to acting and had a classical training attending Drama Studio London, where she performed in plays by Shakespeare, Shaw and Chekhov. She won the “Most Promising Student" of the year award.

Downey played the role of Jacqueline Kennedy Onassis in the American television miniseries A Woman Named Jackie (1991) which won the Emmy Award for Outstanding Miniseries in 1992.

Her role as Jacqueline Kennedy led to her most famous role, as the angel Monica, on the CBS series Touched by an Angel, opposite singer-actress, Della Reese, which ran from 1994 to 2003. She had never been a Della Reese fan, growing up, and won the role.

She is married to television Producer Mark Burnett. She has three children, two step-sons, James Burnett and Cameron Burnett, and her daughter, Reilly Marie Downey Anspaugh (born 3 June 1996) from her previous marriage to Director David Anspaugh. She was also previously married to actor Leland Orser. Reilly is named after her grandmother, Maureen O'Reilly Downey. On Thanksgiving Day 2006, Burnett proposed to Downey during a family vacation in Zihuatanejo, Mexico. They wed on 28 April 2007 in their Malibu home. Her Touched by an Angel co-star, Della Reese, officiated at the wedding.

In 1999, Downey signed with RCA Victor Records and recorded a CD called Healing Angel, released on 14 September 1999.

Downey was raised a Roman Catholic. On 18 April 2009, Downey and Burnett delivered the keynote address and accepted an honorary doctorate of law at Pepperdine University's Graziadio School of Business and Management commencement ceremony. In 2010, Downey graduated from the University of Santa Monica with a master's degree in Spiritual Psychology. Downey also has two honorary degrees; a Doctor of Fine Art (DFA) from the University of Ulster for her outstanding contribution to acting and philanthropy and a Doctor of Letters from Nyack College.

Downey also produced and starred in television movies including Borrowed Hearts and Second Honeymoon. During the run of Touched by an Angel, she recorded the spoken-word album Healing Angel. and wrote the children's book Love Is A Family. She also coauthored a book with her husband "A Story of God and All of Us". She hosted It's a Miracle (TV series), on the Pax Network and appeared on stage in A Picasso at the Geffen Theatre in Los Angeles. She portrayed Annie Sullivan in the TV movie Monday After the Miracle (1998). She has hosted Saturday Night Live, was one of People Magazine's most beautiful people. She is a spokesperson for the volunteer group "Operation Smile". In 2009, she starred in the movie Come Dance at My Wedding alongside John Schneider. On 16 July 2011, She appeared with Actress Marion Ross in the made-for-TV movie Keeping up with the Randalls, broadcast on the Hallmark Channel. Downey is the executive Producer of the animated video series, Little Angels, which was released on DVD with 20th Century Fox Home Entertainment on February 14, 2012.

In December 2013, CBS announced a new miniseries with Downey and her husband, Mark Burnett, The Dovekeepers based on the New York Times Bestseller by Alice Hoffman. The miniseries aired in 2015. In September 2014, MGM acquired a 55% interest in One Three Media and Lightworkers Media. The two companies consolidated into a new film and television company, United Artists Media Group. Burnett became UA's CEO and Downey became President of LightWorkers Media.

The Bible has been watched by over 100 million viewers in the United States alone The series has been the number one downloaded series in iTunes and ranked on Amazon's best sellers in movies and television. A theatrical release was released on 28 February 2014 in the United States, under the title Son of God. The Bible was nominated for the 2013 Primetime Emmy Award, Outstanding Miniseries or Movie.' Downey played the role of Mary, the mother of Jesus. The Bible was filmed in 2012 in Morocco.

Downey is a "Smile Ambassador" for the non-profit organization Operation Smile which provides surgeries for children around the world who were born with severe cleft lip and palate. She has traveled on several international missions with the group to Vietnam, Honduras, and Jordan. She supported the unsuccessful candidacy of Martin McGuinness for President of Ireland in 2011. Downey received the Sally Award by the Salvation Army for her contribution to entertainment and helping those in need on 1 October 2015.

Downey executive produced a re-telling of Ben-Hur, starring Jack Huston, which was released in August 2016.

Downey has also spoken of her deep and lasting love for Della Reese who is like a Mother to her “There is no safer place in the world than in the loving arms of Della Reese." During her nine seasons on-air, she developed a chemistry with Reese and the two struck up a friendship that has lasted. The two remained close until Reese's death on November 19, 2017. On August 11, 2016, just one year before she lost her acting mentor, Reese, along with Downey's husband, Mark Burnett and Pastor Rick Warren were all participants of Downey, to unveil her star on the Hollywood Walk of Fame, next to her husband's. Then, only 4 months after her TV boss's death, Downey said in a 2018 interview with E! Online, after she lost Della was: "I miss her everyday. She was such a blessing in my life but not just my life but the lives of everyone she met." She also added: "She was such an influence on my life. She was my mother. I was a girl without a mother and for certain God brought her into my life. She was one of the lasting gifts of Touched by an Angel."

Downey’s newest book, Box of Butterflies, is set for release in March 2018.