The show was distributed by Debmar-Mercury and aired nationally, with Fox's owned-and-operated stations serving as its primary affiliate base.

The program is formatted as an entertainment-based talk show, focusing largely on celebrity news and gossip as well as lifestyle features.

Each episode begins with "Hot Topics", an opening segment — usually running 18 to 21 minutes (originally lasting 10 to 12 minutes until the third season), depending on the number of stories featured — in which Williams mainly discusses tabloid headlines and celebrity news, provides her opinions, often addressing the celebrities directly and giving them advice to the camera.

Periodic segments-within-a-segment are featured during "Hot Topics" including "Wendy's Got You Covered" (detailing cover stories from current issues of entertainment, fashion and lifestyle magazines), the "Hot Shot of the Day" (showcasing a particular celebrity photo), the "Clip of the Day" (usually featuring clips or promos from upcoming television programs) and "Celebrity Shout-Out" (detailing a celebrity-related story highlighting a particular milestone or accomplishment).

On Mondays, the show regularly features product giveaways, usually as part of "Trendy@Wendy", a weekly segment showcasing fashion/beauty products and electronics that are given to studio audience members, with at-home viewers being able to purchase the featured items through the show's website at a discount from their estimated retail price.

The Wendy Williams Show premiered on July 14, 2008, as a six-week trial run on four Fox-owned outlets: WNYW/New York City, KTTV/Los Angeles, WJBK/Detroit and KDFW/Dallas-Fort Worth.

Following further speculation on her health in late 2018, Williams went on an indefinite hiatus in January and February 2019 after a shoulder injury and worsening complications from Graves' disease and other personal issues.

This time around, several guest hosts such as Jerry O'Connell, Nick Cannon, Keke Palmer, Michael Rapaport, Sherri Shepherd, and Jason Biggs filled the slot until Williams returned on March 4, 2019.

It was later announced that the season would premiere on October 18, 2021, with guest hosts such as Leah Remini, Michelle Visage, Whitney Cummings, Michelle Buteau, Sherri Shepherd, Michael Rapaport, Kym Whitley, Finesse Mitchell, Jerry Springer, Steve Wilkos, Remy Ma, Fat Joe, Michael Yo, Devyn Simone, Bevy Smith, Terrence J, Carson Kressley, Vivica A.

[34] Debmar-Mercury stated that "we believe it is best for our fans, stations and advertising partners to start making this transition now", and that "we hope to be able to work with Wendy again in the future, and continue to wish her a speedy and full recovery.

[37] The show's YouTube channel and all the other social media accounts were deleted and related website domains were relinquished by early July.

Although Williams has stated her support for Beyoncé several times, she has made several comments that have upset the singer's fan group "The Beyhive".

[45] In reference to Harwick's former engagement to The Price Is Right host Drew Carey, Williams joked using the show's catchphrase, "Come on down!"

[47] In a May 2021 segment discussing Ellen DeGeneres announcing her talk show would be ending the following year, Williams stated she believed that DeGeneres was actually leaving due to negative publicity surrounding a July 2020 investigation into allegations of the series' work environment; the investigation ultimately led to WarnerMedia firing three executive producers of the show.

[48][49][50] On February 13, 2020, Williams was accused of homophobia and transphobia during a segment discussing the unofficial Galentine's Day holiday, where she told gay men to "stop wearing our skirts and heels" and that one must menstruate "to be a woman."