Her feature film debut came in 1959 as Linda Davis in 4D Man, starring Robert Lansing.
Man from UNCLE, 1964, The Mad, Mad Tea Party cameo as Dr. Egert. Meriwether portrayed Catwoman for the 1966 Batman movie and co-starred as scientist Dr. Ann MacGregor in the 19661967 television series The Time Tunnel. In the late 1960s and early 1970s, she had guest starring roles in numerous TV series, including the CBS anthology, The Lloyd Bridges Show, Star Trek episode That Which Survives and the F Troop episode O'Rourke vs. O'Reilly. In films, she joined John Wayne and Rock Hudson for The Undefeated, and Andy Griffith in Angel in My Pocket in 1969. In the same year, she played IMF spy Tracey Fielding in six Mission: Impossible episodes (in season four), after Barbara Bain's departure.
She began her best-known role as private detective Betty Jones in the 19731980 CBS series Barnaby Jones, opposite Buddy Ebsen. During the show's eight-year run, she enjoyed an on- and off-screen chemistry with the elder Ebsen. During the show's run, she was reunited with former classmate and best friend Bill Bixby on one episode. After her stint on Barnaby Jones, Meriwether became best friends and kept Ebsen in touch for many years until his own death on July 6, 2003. She is best known in the UK for her portrayal of Lily Munster in the 1988 remake of The Munsters, The Munsters Today, in which she starred alongside Jason Marsden, John Schuck, Howard Morton and Hilary Van Dyke.
In the 1970s and 1980s, Meriwether appeared on Circus of the Stars four times. She also served as a panelist on the game show Match Game.
Starting January 8, 1971, Lee Meriwether accompanied Andy Griffith in a short-lived series called The New Andy Griffith Show, as his wife Lee (along with their two children).
Between 198891, she had a three-year run as Lily Munster opposite John Schuck's Herman in The Munsters Today.
In the 1990s, she appeared as herself on an episode of Space Ghost: Coast to Coast. She had a memorable exchange with Zorak, in which she said, For my money, Eartha [Kitt] was the best Catwoman. Zorak, portraying the evil Batmantis, replied, Give me your money, followed by a Batman-esque sound effect.
In 1996, Meriwether took over for Mary Fickett in the role of Ruth Martin on the soap opera All My Children. Fickett had occupied the role since its inception in 1970. After 26 years she wanted to go into semi-retirement as a recurring cast member. Negotiations with higher powers broke down and Meriwether was recast as Ruth Martin. In 1999, ABC deemed that they were at an impasse with Meriwether's agents. Mary Fickett was then brought back as a recurring cast member. Fickett called it quits for good in December 2000. ABC wanted to bring back the character of Ruth Martin in 2002 but Fickett remained in retirement. Meriwether was brought back and has been on periodically to date.
She also appeared Off Broadway in the interactive comedy, Grandma Sylvia's Funeral.
Meriwether also voiced EVA in the video game Metal Gear Solid 4: Guns of the Patriots for the PlayStation 3. She also appears in one of the game's opening videos. Here she plays a talk show host having an interview with David Hayter, who voices Solid Snake.
In 2008, Meriwether had a brief cameo as comic book character Battle Diva in the episode Harper Knows of the Disney Channel original series Wizards of Waverly Place.