In July 1849, Barlow Granger began the paper in an abandoned log cabin by the junction of the Des Moines and Raccoon River.

During the 1960s, circulation of the Register peaked at nearly 250,000 for the daily edition and 500,000 for the Sunday edition–more than the population of Des Moines at the time.

Another Register tradition – the sponsorship of RAGBRAI – began in 1973 when writer John Karras challenged columnist Donald Kaul to do a border-to-border bicycle ride across Iowa.

[citation needed] In 1985, faced with declining circulation and revenues, the Cowles family sold off its various properties to different owners, with the Register going to Gannett.

[citation needed] The Register opened a new printing and distribution facility on the south side of Des Moines in 2000.

The Register came under scrutiny in September 2019 after uncovering a pair of controversial tweets made by Carson King, a 24-year-old Iowa man whose beer sign on ESPN College GameDay resulted in over $3 million in contributions to a children's hospital.

According to Carol Hunter, the paper's executive editor, the Register elected to include the information toward the end of a story about King.

But rest assured such decisions are not made lightly and are rooted in what we perceive as the public good," she explained after receiving complaints from readers.

[6] Some readers later found social media comments previously made by the reporter, Aaron Calvin, which contained racial slurs and condemnation of law enforcement.

[7] The Register defended its decision and announced that they would launch an investigation into the "inappropriate social media posts" made by a staff member, though it did not name anyone involved.

[9] Calvin later wrote an op-ed in the Columbia Journalism Review blaming Gannett and the Register for what he considered to be an "unfair" firing.

[10][11] In October 2022, the Register was discovered to have provided commercial printing services[12] to a "pink slime" media client, Local Government Information Services, which the Columbia Journalism Review described as publishing "multiple misleading, decontextualized, and often nonfactual stories on hot-button issues in Illinois".

[15] The new owners presented a variety of viewpoints, including Darling cartoons that frequently made fun of progressive politicians.

The Register endorsed Romney over Obama ten days before the general election on October 27, 2012, the first time that it supported a Republican for president since 1972.

[26][27] On January 23, 2016, it endorsed Republican Senator Marco Rubio for the GOP nomination and Hillary Clinton for the Democratic candidate.

On October 13, 2018, the Register endorsed all Democratic candidates standing for the House of Representatives in the 2018 elections and stated that Republicans have "failed to govern".

At its peak, the syndicate offered other newspapers some 60 to 75 features, including editorial cartoonist Herblock and commentaries by David Horowitz, Stanley Karnow, and others.

This was a tabloid-sized newsprint comic book sold as part of eventually 20 Sunday newspapers with a combined circulation of as many as five million copies.

[30] Brianne Pfannenstiel was selected chief politics reporter for the 2020 United States presidential election and co-moderated the seventh Democratic debate with Wolf Blitzer and Abby Phillip on January 14, 2020.

Register writer Clark Kauffman was one of three finalists for the 2005 Pulitzer Prize for Investigative Reporting for his exposure of glaring injustice in the handling of traffic tickets by public officials in Iowa.