The station's first broadcast was a baseball game between the St. Louis Browns and Cincinnati Reds, announced by Buddy Blattner, Bill Durney and Milo Hamilton.

It moved its operations to facilities located in the Clayton-Tamm/Dogtown neighborhood in west St. Louis (off present-day I-64/US 40 at the intersection of Berthold, Oakland, and Hampton Avenues).

However, the Federal Communications Commission (FCC) had recently changed its regulations so that the station could have kept its license in Belleville even while moving its main studio to St. Louis.

The station lost DuMont programming when the network ceased operations in 1956, making KTVI an exclusive ABC affiliate.

In March 1993, in order for the company to concentrate on its newspaper and cable television system franchises, Times Mirror sold KTVI and its three sister stations—fellow CBS affiliates KTBC in Austin and KDFW-TV in Dallas–Fort Worth and NBC affiliate WVTM-TV in Birmingham—to Argyle Television Holdings in a two-part deal for $335 million in cash and securities.

(WVTM did not switch as WBRC, which was placed in a blind trust, was later sold to Fox outright as New World could not keep both due to FCC rules at the time that forbade duopolies).

[10][11] The deal was motivated by the National Football League (NFL)'s awarding of the rights to the National Football Conference (NFC) television package to Fox on December 18, 1993, in which the conference's broadcast television rights moved to the network effective with the 1994 NFL season, ending a 38-year relationship with CBS.

Of ABC's options, four prospects were automatically eliminated: KSDK was in the middle of a long-term affiliation agreement between its owner at the time, Multimedia Broadcasting, and NBC; KMOV was under a long-term agreement between CBS and Paramount Stations Group (which was in the process of selling KMOV and its four other major network affiliates to focus on its Fox-affiliated and independent stations that were set to become charter affiliates of group parent Viacom's then-upstart United Paramount Network [UPN]); and KNLC (channel 24, now a MeTV owned-and-operated station) and WHSL (channel 46, now Ion Television O&O WRBU) were respectively owned by the locally based New Life Christian Church and the Home Shopping Network at the time, and both stations had inferior signals, even on cable, making either unlikely choices as even last-ditch options.

[citation needed] As with most of the other New World-owned stations affected by the agreement with Fox, KTVI retained its longtime "Channel 2" branding upon the affiliation switch, with references to the Fox logo and name limited in most on-air imaging; it also retained the news branding it had been using before it joined the network—in its case, The 2 News Team, which the station adopted in November 1990 as an ABC affiliate.

Subsequently, on June 2, 2008, KTVI launched GarageSaleSTL.com, a free website that primarily features a Google-based map of viewer-submitted garage sales (the site has since been discontinued).

On December 22, 2007, Fox sold KTVI and seven other owned-and-operated stations—WDAF-TV in Kansas City, WBRC in Birmingham, WGHP in Greensboro–Winston-Salem–High Point, WJW in Cleveland, WITI in Milwaukee, KDVR in Denver and KSTU in Salt Lake City—to Local TV (a broadcast holding company operated by private equity firm Oak Hill Capital Partners that was formed on May 7 of that year to assume ownership of the broadcasting division of The New York Times Company) for $1.1 billion; the sale was finalized on July 14, 2008.

On July 1, 2013, the Tribune Company (which in 2008, had formed a joint management agreement involving its Tribune Broadcasting subsidiary and Local TV to operate stations owned by both companies and provide web hosting, technical and engineering services to those run by the latter group) acquired the Local TV stations for $2.75 billion;[19] the sale was completed on December 27.

(In recent years, KPLR and KDNL – which ranked fourth in the ratings at that time – have rotated between fourth and fifth place in total day viewership due to the weaker viewership of KDNL's programming since its news department was shut down by owner Sinclair Broadcast Group in 2001); St. Louis also has only nine full-power television stations, seven of which are commercial outlets, making this the only legal duopoly allowable in the market under FCC rules.

[26][27] Prohibited from owning all three stations, Sinclair would have been required to sell KPLR to a third party to comply with ownership rules and alleviate potential antitrust issues.

Fox prime time shows preempted or otherwise interrupted by such content may either be rebroadcast on tape delay over KTVI's main channel in place of syndicated programs normally shown during overnight timeslots.

Station personnel also gives viewers who subscribe to AT&T U-verse, DirecTV, Dish Network and other pay television providers within the KTVI viewing area the option of watching the affected shows on the Fox Now streaming platforms or its cable/satellite video-on-demand service the day after their initial airing.

[43] KNLC then drew the ire of the network by asking children to write to Missouri governor Mel Carnahan to protest the planned execution of Johnny Lee Wilson, then in prison for the 1986 murder of 79-year-old Aurora resident Pauline Martz[44] (Carnahan pardoned Wilson that same month[45]); additionally, KNLC's poor signal—both over the air and on cable—angered members of the largest Fox Kids Club in the nation.

Fox discontinued its weekday block nationwide on December 31, 2001,[49] while the Saturday lineup was contracted out to 4Kids Entertainment and relaunched as FoxBox on September 14, 2002.

On February 15, 2009, KTVI began broadcasting local newscasts in high definition from its new Maryland Heights studio, accompanied by a new graphics package.

The set was updated with several elements added to better fit the new graphics and due to the conversion to HD, while removing the city skyline backdrop in favor of a blue background.

On January 28, 2015, both stations introduced a new combined set with LED lighting, two video walls (one replacing the weather green screen), and a new anchor desk.

[54] KTVI became the first station in the Central Time Zone to launch an 11 p.m. weeknight newscast Hosted by Shirley Washington and Jasmine Huda (formerly of KMOV) the show debuted on January 18, 2016.

In February 2021, both stations overhauled their set again with an expansion of the physical studio space with multiple venues and a larger video wall.