Saint was born in Newark, New Jersey, to Quaker parents: Eva Marie (née Rice; 1896–1987) and John Merle Saint (1891–1965). She attended Bethlehem Central High School in Delmar, New York, near Albany, graduating in 1942. She was inducted into the high school’s hall of fame in 2006. She studied acting at Bowling Green State University and joined Delta Gamma Sorority. During this time she played the lead role in a production of Personal Appearance. A theater on Bowling Green’s campus is named after her. She was an active member in the theater honorary fraternity, Theta Alpha Phi, and served as record keeper of the student council in 1944.

She appeared in a 1947 Life Magazine special about television, and also in a 1949 feature Life article about her as a struggling actress earning minimum amounts from early TV while trying to make ends meet in New York City. In the late 1940s, Saint continued to make her living by extensive work in radio and television. In 1953, she won the Drama Critics Award for her Broadway stage role in the Horton Foote play, The Trip to Bountiful (1953), in which she co-starred with such formidable actors as Lillian Gish and Jo Van Fleet.

Saint’s introduction to television began as an NBC page. She appeared in the very early live NBC TV show Campus Hoopla in 1946–47. Her performances on this program are recorded on rare kinescope, and audio recordings of these telecasts are preserved in the Library of Congress. She also appeared in the Bonnie Maid’s Versa-Tile Varieties on NBC in 1949 as one of the original singing “Bonnie Maids” used in the live commercials.

Saint married producer and director Jeffrey Hayden on October 28, 1951. They had two children together: son Darrell Hayden (born 1955) and daughter Laurette Hayden (born 1958). Their first child, Darrell, was born two days after she won an Academy Award for On the Waterfront. They were married for 65 years until Hayden’s death on December 24, 2016, at the age of 90.

In 1955, Saint was nominated for her first Emmy for “Best Actress In A Single Performance” on The Philco Television Playhouse, for playing the young mistress of middle-aged E. G. Marshall in Middle of the Night by Paddy Chayefsky. She won another Emmy nomination for the 1955 television musical version of Our Town, adapted from the Thornton Wilder play of the same name. Co-stars were Paul Newman and Frank Sinatra. Her success and acclaim in TV productions were of such a high level that “One slightly hyperbolic primordial TV critic dubbed her ‘the Helen Hayes of television.'”

She appeared alongside Bob Hope in That Certain Feeling (1956) for which she received $50,000. She was then offered $100,000 to star in the lavish Civil War epic Raintree County (1957) with Elizabeth Taylor and Montgomery Clift. After that, she starred with Don Murray in A Hatful of Rain, the pioneering drug-addiction drama, which although made later than Raintree Country was released earlier in 1957. She received a nomination for the “Best Foreign Actress” award from the British Academy of Film and Television for her performance.

Saint was soon back on the small screen in numerous projects. After receiving five nominations, she won her first Emmy Award for the 1990 miniseries People Like Us. She appeared in a number of television productions in the 1990s and was cast as the mother of radio producer, Roz Doyle, in a 1999 episode of the comedy series Frasier.

In a 2000 interview in Premiere magazine, Saint recalled making the film, which has been highly influential, saying, “[Elia] Kazan put me in a room with Marlon Brando. He said ‘Brando is the boyfriend of your sister. You’re not used to being with a young man. Don’t let him in the door under any circumstances.’ I don’t know what he told Marlon; you’ll have to ask him—good luck! [Brando] came in and started teasing me. He put me off balance. And I remained off balance for the whole shoot.”, she explained the same anecdote in a 2010 interview.

In 2000, recalling her experience making the picture with Cary Grant and Hitchcock, Saint said, “[Grant] would say, ‘See, Eva Marie, you don’t have to cry in a movie to have a good time. Just kick up your heels and have fun.’ Hitchcock said, ‘I don’t want you to do a sink-to-sink movie again, ever. You’ve done these black-and-white movies like On the Waterfront. It’s drab in that tenement house. Women go to the movies, and they’ve just left the sink at home. They don’t want to see you at the sink.’ I said, ‘I can’t promise you that, Hitch, because I love those dramas.'”, she also recalled it in 2010.

In 2000, Saint returned to feature films in I Dreamed of Africa with Kim Basinger. In 2005 she co-starred with Jessica Lange and Sam Shepard in Don’t Come Knocking. Also in 2005, she appeared in the family film Because of Winn-Dixie, co-starring AnnaSophia Robb, Jeff Daniels, and Cicely Tyson.

In 2006, Saint appeared in Superman Returns as Martha Kent, the adoptive mother of Superman, alongside Brandon Routh and a computer-generated performance from her On the Waterfront co-star Marlon Brando.

She was presented one of the Golden Boot Awards in 2007 for her contributions to western cinema.

Saint has appeared in a number of television specials and documentaries, particularly since 2000. These include The Making of North by Northwest, which she narrated and hosted. In 2009, she made a rare public appearance at the 81st Academy Awards ceremony as a Best Supporting Actress presenter. In 2011, Saint participated in two screenings of North by Northwest with Robert Osborne. The films were shown in Seattle and Cleveland. Saint and Osborne participated in meet-and-greet sessions as well as a pre-movie question and answer session.

In September 2012, she was cast as the adult version of Willa in the film adaptation of the novel Winter’s Tale by Mark Helprin. The film was released on Valentine’s Day 2014.