In 1959, Wells was crowned Miss Nevada and represented her state in the Miss America 1960 pageant in Atlantic City, New Jersey.

In Hollywood, Wells made her debut on ABC's The Roaring 20s and the movie The New Interns and was cast in episodes of such television series as The Joey Bishop Show, 77 Sunset Strip, The Cheyenne Show, Maverick, and Bonanza, before she took the role of Mary Ann on Gilligan's Island. She reprised her character in the various Gilligan's Island reunion specials, including the reunion cartoon spin-off Gilligan's Planet and three reunion movies: Rescue from Gilligan's Island, The Castaways on Gilligan's Island, and The Harlem Globetrotters on Gilligan's Island.

She also appeared as a guest star on Wagon Train, Tales of Wells Fargo, 87th Precinct, Surfside 6, Hawaiian Eye, Ripcord, The Everglades, The Detectives, It's a Man's World, Channing, Laramie, Burke's Law, The Invaders, The Wild Wild West, The F.B.I., Vega$, The Love Boat, Fantasy Island, Matt Houston, ALF, Herman's Head, Three Sisters, Pastor Greg, and Roseanne.

Wells had small roles in the early 1960s films Palm Springs Weekend and The New Interns, and later starred with Michael Dante in the independent 1975 film Winterhawk, playing a Western settler kidnapped by a Native Ametican chief. Her other films include The Town That Dreaded Sundown, Return to Boggy Creek, Lover's Knot, Soulmates, Forever for Now, and Super Sucker. In fall 2011, she began filming Silent But Deadly (originally titled Hotel Arthritis), a comedy horror film released in 2012.

Following Gilligan's Island, Wells embarked on a theater career, appearing in nearly one hundred theatrical productions as of July 2009. She spent the majority of the 1970s, and 1980s, touring in musical theater productions. She also had a one-woman show at the MGM Grand Hotel and Casino in Las Vegas in 1985.

In 1993, Wells published Mary Ann's Gilligan's Island Cookbook with co-writers Ken Beck and Jim Clark, including a foreword by Bob Denver. She was close to Alan Hale Jr., who played The Skipper on Gilligan's Island, even after the series completed its run, and he contributed a family recipe ("Kansas Chicken and Dumplings") to her cookbook. Hale's character was the inspiration behind such concoctions as Skipper's Coconut Pie, Skipper's Navy Bean Soup, and Skipper's Goodbye Ribeye, and he is depicted as Skipper Jonas Grumby in numerous photographs throughout the book. She said in a 2014 interview with GoErie.com, "Alan could not have been kinder to a young actress. He was a real peach."

In 2005, Wells consigned her original gingham blouse and shorts ensemble for sale from her signature role. Beverly Hills auction house Profiles in History sold it for $20,700.

In 2014, Wells released What Would Mary Ann Do? A Guide to Life, which she co-wrote with Steve Stinson. The book was released to coincide with the 50th anniversary of Gilligan's Island.

In May 2016, Wells was named Marketing Ambassador to MeTV Network. In January 2019, she promoted the Gilligan's Island television series on the MeTV television network.