Sheridan made her debut in the short-lived US primetime soap opera Paper Dolls in 1984, but her breakthrough came in 1986, when she joined the cast of the CBS primetime soap Knots Landing as "Paige Matheson". She started out in a recurring role, but proved to be so popular that she was a series regular by the 1988-89 season. For her performance in the role, she won the 1990 Soap Opera Digest Award for "Outstanding Lead Actress: Prime Time" and the 1991 Soap Opera Digest Award for "Outstanding Heroine: Prime Time". The same year, she was named one of People Magazine's "50 Most Beautiful People". After the series ended in 1993, she appeared in several made-for-TV movies and the films Spy Hard and Beverly Hills Ninja and auditioned for the role of Grace Adler on Will & Grace (on which she would later guest-star). Despite her carefully cultivated sex symbol image, Sheridan has only done one nude scene during her career, in the low budget 1999 film Raw Nerve, opposite Mario Van Peebles. In 2004, Sheridan's role as sexy divorcee Edie Britt in ABC's Desperate Housewives brought her renewed media attention. She was nominated for a 2005 Golden Globe Award for Best Supporting Actress and was named #48 on Maxim's 2006 List. Less positively, she was named 2004's "worst dressed" by Mr. Blackwell. Blackwell's citation probably resulted from the colourful and boldly-cut gown Sheridan wore as a presenter at the American Music Awards on November 14, 2004 but he had earlier (TV Guide, July 22, 1989) praised her fashion sense: "daring ... with her panache, she brings it off without a hitch. For the adventurer in all of us, she's the one to watch".

On November 15, 2004, Sheridan was cited by the FCC for her appearance in a sketch that opened the evening's Monday Night Football broadcast. The Desperate Housewives-inspired sketch, showing Sheridan dropping a towel to attract the attention of football player Terrell Owens who then said "ah hell", was widely condemned as being sexually suggestive. ABC was forced to apologize for airing it, but the citation against Sheridan was dropped on March 14, 2005. On November 22, 2004, World Wrestling Entertainment (WWE) aired a controversial parody showing WWE Diva Trish Stratus dropping her towel to attract WWE Superstar Shelton Benjamin, but being caught in the act by the company's chairman, Vince McMahon. Todd Schnitt of radio station WFLZ-FM in Tampa, Florida, placed an early-morning telephone call to Sheridan on November 18, 2004, waking her to discuss the Monday Night Football controversy (which had come to be called "Towelgate"). On January 30, 2007, the FCC levied a $10,000 fine because the station violated regulations in failing to inform Sheridan that the interview was being broadcast. Toward the close of the fourth season of Desperate Housewives, conflicting reports circulated regarding Sheridan's future in her role. While Hollywood.com reported in April that series creator Marc Cherry had said Sheridan would depart at the end of the season, another source stated that Sheridan was confident she would return for the series' fifth season. By May 4, Entertainment Weekly reported that Sheridan would likely make several appearances in the upcoming season, but not necessarily as a regular cast member.

Actress Dana Delany, who plays Katherine Mayfair, confirmed that Nicollette Sheridan would be back to reprise her role for Season 5 of Desperate Housewives, and the Hollywood Reporter reported Nicollette's character might be seducing another boyfriend, played by actor Neal McDonough. When season five aired, Sheridan did indeed reprise her regular role as Edie, now married to to McDonough's character. In February 2009 Sheridan announced she will be leaving Desperate Housewives at the end of the season. Her final episode will be in April 2009. And according to E! Online Sheridan's character Edie Britt will be killed off the show. "If there are no script changes, Edie will die before the season ends. She will find out that Dave plans to kill her. When he tries to, Edie escapes only to get involved in an accident that involves her car and an electrical wire." Actress Dana Delany, who plays Katherine Mayfair, confirmed that there will be some shocking drama when Nicollette Sheridan leaves the show. According to Dana Delany, a party is the best way to say farewell to Nicollette Sheridan.

• Noah's Ark: The New Beginning (2008) (post-production) (voice) .... Zenna
  
• "Desperate Housewives" .... Edie Britt (110 episodes, 2004-2009)
       - The Story of Lucy and Jessie (2009) TV episode .... Edie Britt
       - Crime Doesn't Pay (2009) TV episode .... Edie Britt
       - In a World Where the Kings Are Employers (2009) TV episode .... Edie Britt
       - Mama Spent Money When She Had None (2009) TV episode .... Edie Britt
       - The Best Thing That Ever Could Have Happened (2009) TV episode .... Edie Britt
        (105 more)
• Fly Me to the Moon (2008) (voice) .... Nadia
  ... aka Fly Me to the Moon 3D (USA: new title)
• Code Name: The Cleaner (2007) .... Diane
  ... aka The Cleaner (USA: informal short title)
• The Karate Dog (2004) (TV) (voice) .... White Cat
• Deadly Visions (2004) (TV) .... Ann Culver
  ... aka Deadly Visions (USA)
  ... aka Possessed (USA: DVD title)
• "Becker" .... Anna (1 episode, 2003)
       - A First Class Flight (2003) TV episode .... Anna
• "Will & Grace" .... Dr. Danielle Morty (1 episode, 2003)
       - 24 (2003) TV episode .... Dr. Danielle Morty
• Lost Treasure (2003) .... Carrie
• "Static Shock" .... Darcy / ... (1 episode, 2003)
       - Toys in the Hood (2003) TV episode (voice) .... Darcy/Miss Moore
• Tarzan & Jane (2002) (V) (voice) .... Eleanor
• Haven't We Met Before? (2002) (TV) .... Eliza/Kate/Emily Winton
  ... aka Mary Higgins Clark's 'Haven't We Met Before?' (Canada: English title)
  ... aka Mary Higgins Clark's Haven't We Met Before? (Australia: DVD title)
  ... aka Mary Higgins Clark: Vous souvenez-vous? (Canada: French title)
• .com for Murder (2002) .... Misty Brummel
• Deadly Betrayal (2002) (TV) .... Donna Randal
  ... aka Trahison mortelle (Canada: French title)
• "The Legend of Tarzan" .... Eleanor (28 episodes, 2001)
  ... aka Disney's the Legend of Tarzan (USA: complete title)
       - Tarzan and Tublat's Revenge (2001) TV episode (voice) .... Eleanor
       - Tarzan and the Mysterious Visitor (2001) TV episode (voice) .... Eleanor
       - Tarzan and the Gauntlet of Vengeance (2001) TV episode (voice) .... Eleanor
       - Tarzan and the Missing Link (2001) TV episode (voice) .... Eleanor
       - Tarzan and the Face from the Past (2001) TV episode (voice) .... Eleanor
        (23 more)
• The Spiral Staircase (2000) (TV) .... Helen Capel
  ... aka Secret du manoir, Le (Canada: French title)