Waldo was born in Yakima, Washington in 1919. Her mother, Jane Althea Blodgett, was a singer trained at the Boston Conservatory of Music, and her father, Benjamin Franklin Waldo, was, according to Waldo family lore, a distant cousin of Ralph Waldo Emerson. Her elder sister, Elisabeth Waldo, is an authority on pre-Columbian music and an award-winning composer-violinist who appeared in the film Song of Mexico (1945).

In 1948, the Meet Corliss Archer comic book, using Waldo's likeness, published by Fox Feature Syndicate, appeared for a run of three issues from March to July 1948, using the original scripts. On April 1, 1948, Waldo married Playwright Robert Edwin Lee, the writing partner of Jerome Lawrence. The couple had two children, and remained married until his death in 1994.

She co-starred with Jimmy Lydon in the CBS situation comedy Young Love (1949–50), and she had recurring roles on The Adventures of Ozzie and Harriet (as teenager Emmy Lou), The Red Skelton Show and People Are Funny. She recorded with jazz vocalist Mel Torme and his vocal group the Mel-Tones.

Waldo made a rare on-screen television appearance when she appeared as Peggy, a teen smitten with Ricky Ricardo on a 1952 episode of I Love Lucy titled "The Young Fans" with Richard Crenna. Ten years later, Waldo again worked with Lucille Ball, this time playing Lucy Carmichael's sister, Marge, on The Lucy Show. That episode was titled "Lucy's Sister Pays A Visit". She also appeared on an episode of The Andy Griffith Show as Amanda. Waldo also reprised the role of Emmy Lou for some early TV episodes of The Adventures of Ozzie and Harriet. Later, she was the female lead opposite Anthony Franciosa in the short-lived sitcom Valentine's Day (1964).

In television animation, she played Judy Jetson in all versions of the Hanna-Barbera television series The Jetsons. Waldo was the last surviving main cast member of the original The Jetsons series. In 1964–66, she took over the role of Pearl Slaghoople on The Flintstones, which was originally played by Verna Felton. Waldo reprised Mrs. Slaghoople on the Flintstones TV films I Yabba-Dabba Do! and Hollyrock-a-Bye Baby in the 1990s.

Further guest starring roles include Beth Crane, a descendant of Ichabod Crane, in the episode "The Headless Horseman of Halloween" from The Scooby-Doo Show in 1976 and as Aggie Wilkins/Witch McCoy in the episode "The Ozark Witch Switch" in 1977. The following year she voiced both Arlene Wilcox, twin sister of the 'Witch of Salem' and the witch in the episode "To Switch a Witch " from the third season of Scooby Doo, Where Are You? in 1978. She voiced Morticia Addams in the short-lived 1973 cartoon series adaptation of The Addams Family. Waldo was the voice of Princess and Susan in the English-language version of Kagaku ninja tai Gatchaman, known as Battle of the Planets, and Hogatha in The Smurfs.

In 1990, shortly after completing her role as Judy Jetson in Jetsons: The Movie, she was abruptly replaced with pop star Tiffany. The executive decision of Universal Pictures caused casting Director Andrea Romano to say it was "a huge mistake on so many levels" and Romano asked that her name be removed from the credits. Romano received volumes of hate mail despite her stance on the casting change. Voice Director Gordon Hunt reportedly asked Tiffany to sound more like Waldo.

Waldo died on June 12, 2016 at the age of 97. She had been diagnosed with a benign but inoperable brain tumor five years before her death. She is interred at the Forest Lawn Memorial Park in the Hollywood Hills.