In early 1955, the station was purchased by the Hearst Corporation, publishers of The Milwaukee Sentinel and owners of WISN radio (1130 AM); the new owners changed channel 12's call letters to WISN-TV, after its radio sister (whose calls were derived from now-defunct newspaper The Wisconsin News.

[4] During channel 12's time with CBS, it was the home station for the NFL's Green Bay Packers for the Milwaukee market, airing the team's first two Super Bowl appearances.

Meanwhile, ABC had become the top-rated television network in the United States, thanks in large part to two Milwaukee-set sitcoms: Happy Days and Laverne & Shirley.

Around the same time, the station was the first which utilized newscast composer Frank Gari's "Hello News" package, which included an imaging song individualized to each market's city; in this case "Hello Milwaukee", which remains well-remembered and remains used in various ways by WISN-TV to the present day, and was cited as one of the factors in driving viewers to the station in the late 1970s and allowing it to be competitive.

Channel 12 was the first commercial station in the market to produce a high-definition broadcast, airing the Summerfest "Big Bang" fireworks show in HD on June 29, 2006.

During the transition, WLTQ's live on-air personnel, who also acted as hosts for WISN's local programming and Wisconsin Lottery drawings and its game show, The Money Game (allowing the news department to avoid any on-air role with the lottery outside relaying winning numbers), became employees of Clear Channel, and after The Money Game ended production in the mid-2000s, the station virtually ceased local productions not connected to newscasts, advertising, or charity efforts.

All ties between WISN-TV and its former sister radio stations were severed when a longtime agreement with channel 12 to provide forecasts for WISN (AM) and the then-WQBW (now WRNW) and four others within Clear Channel's Milwaukee radio cluster ended on July 27, 2009 (though WRNW continues to transmit from WISN-TV's tower), as WITI began its own weather/news content agreement with the stations.

[10] WISN-TV then began a news content agreement with Saga Communications for its five area radio stations (WKLH, WHQG, WJMR-FM, WJYI and WNRG-FM),[11] along with providing weather forecasts to WGXI in Plymouth.

Due to the now separate ownership of the two stations, WISN-TV's news staff disclaim both on-air and through their social networking channels that the station has no connections with WISN radio's conservative talk format other than sharing the same call letters, a point of contention and confusion during events such as live shots at the Wisconsin State Capitol for the 2011 state budget debate.

On April 30, 2021, the station added a third subchannel carrying Shop LC over-the-air as part of a broader year-long channel carriage agreement between that network's owners and Hearst (ShopLC already purchases several channel slots on pay television providers, thus Hearst does not need to seek cable carriage for that subchannel).

As Hearst and Time Warner Cable entered into a retransmission consent dispute that resulted in Hearst's stations being removed from TWC's systems in certain markets on July 10, 2012, WISN was not immediately removed from its Milwaukee area systems in an eleventh hour announcement, as the direct fiber connection between WISN and TWC was then the same line utilized to Charter Communications; before the two companies merged in 2017 as Spectrum, Charter served the outer portions of the market such as western Waukesha County and most of Washington, Fond du Lac and Sheboygan counties.

The station also carries Monday Night Football games featuring the Green Bay Packers by virtue of Hearst's 20% ownership of ESPN.

The station's biggest hire came when longtime WTMJ anchor Mike Gousha joined channel 12 in 2007, a year after he retired as WTMJ's evening news anchor in order to focus on his new position as a distinguished fellow in law and public policy at Marquette University.

[19] Hearst syndicated the show to other stations statewide, and in August 2010 all of the stations involved (along with Milwaukee Public Television, which provided technical assistance with HD production) broadcast a Gousha-moderated forum for the Wisconsin Republican gubernatorial candidates called the UpFront Town Hall Challenge from Marquette's new law building, which was purposefully structured to avoid classification as a traditional debate where either candidate could use the format to "sell" themselves.

Then on June 28, 2011, WISN-TV became the third station in Milwaukee (behind WTMJ-TV and WITI) to begin broadcasting its newscasts in high definition.