For over a hundred years, the Medford Mail Tribune has argued against what it perceived to be dangerous, irrational, or unfair—if often popular—political measures, facing libel suits, jailings, death threats, and boycotts as a result. The newspaper was created by a 1906 merger of the Southern Oregon Mail, a proponent of political reform published in Medford since 1888, and the Tribune, which began publication in Ashland in 1894. The Mail Tribune earned recognition and respect from journalists for its public service and was the first Oregon newspaper to win a Pulitzer Prize (1934). 

George Putnam, a progressive Democrat and the Oregon Journal’s news editor before moving to Medford in 1907, was the Mail Tribune’s first owner and editor. Among his early editorial campaigns was an effort to improve the city’s drinking water, which he referred to as "so muddy that it is clogging the meters.” Putnam suggested that the city was "obtaining money under false pretenses" by selling polluted water to residents, and published his own eyewitness account of the president of the local railroad company chasing the mayor down Main Street with an ax. He was jailed and convicted of libel; the Oregon Supreme Court reversed the lower-court verdict. "The paper that has no enemies has no friends," Putnam wrote of his ordeal. He not only had been jailed, convicted, and fined, he reported, but also was “slugged on the streets and denied justice by two grand juries.”

Putnam sold the Tribune to Robert Ruhl and S. Sumpter Smith in 1919. As editor, Ruhl proclaimed the paper an independent force for better government in the Rogue River Valley. In the early 1920s, the Mail Tribune editorialized strongly against the increasing influence of the Ku Klux Klan in the state, one of few Oregon newspapers to do so. Facing a boycott of the newspaper by advertisers and Klan supporters, Ruhl hoped that in a "time not far distant, the widespread report that Jackson County is a hot bed of Ku Kluxism, can be finally and permanently denied."

During 1932-1933, in the depth of the Depression, the Mail Tribune survived another boycott and threatened violence by supporters of a local populist insurgency called the Good Government Congress. Led by the demagogic owner and editor of a competing daily, the Medford News, the Good Government Congress episode severely roiled southern Oregon politics and society. Its violent end in early 1933 brought national attention to the region as well as a Pulitzer Prize to the Mail Tribune for its "leadership in pleading for straight-thinking and peace."

Eric W. Allen Jr. took over the editorial reins of the paper in 1964 and soon gained a reputation as a supporter of civil rights, handgun control, land use planning, controls on air and water pollution, and other issues that were unpopular with many Mail Tribune subscribers. Under Allen’s leadership, the newspaper supported progressive candidates for state and national offices regardless of which party they represented. "It's never pleasant to be damned, and I was," Allen wrote, adding, "I'm a good forgetter, too." He was a fervent believer in the First Amendment. "Cherish it as you would your lives,” he wrote, “for without the First Amendment, your lives would almost assuredly be hardly worth living."

After its purchase by Ottaway Newspapers (a subsidiary of Dow Jones) in 1973, the Mail Tribune moved into two new buildings, added a Saturday edition, and became a morning publication. It also dropped "Medford" from its nameplate as it became more of a regional publication. News Corporation bought Dow Jones in 2007 and sold the Tribune in 2013 to Newcastle Investment, which assigned operations to GateHouse Media, which oversees some 400 newspapers and 350 related websites. The Mail Tribune, the Ashland Daily Tidings, and the Nickel (a weekly shopper) now make up the Southern Oregon Media Group, created when News Corporation purchased the three publications. The Mail Tribune and all other Southern Oregon Media Group properties were sold to Rosebud Media LLC in January 2017.

According to former Mail Tribune editor Bob Hunter, the paper remains a strong advocate for Medford and the Rogue Valley, one that does not shy away from what he terms "constructive criticism" of governmental entities. Continuing in the “watchdog” role pioneered by Putnam and carried on by Ruhl and Allen, the newspaper won a number of awards, including being honored by the Oregon Newspaper Publishers Association as the best paper in its circulation class for 2011-2014 and being named GateHouse newspaper of the year in 2014. Hunter retired as Mail Tribune editor effective Sept. 17, 2016. Appointed as his replacement was Cathy Noah, the paper's city editor since 2007. Noah is the first female editor in the Mail Tribune's 110-year history.

Mail Tribune print circulation "has been declining in the past decade," according to Hunter, but, he adds, "online readership has more than offset that, with the unique online visitor numbers exceeding the declines in circulation." Hunter says the Mail Tribune is "definitely a digital-first organization, moving all news—and many features—as they are finished, rather than waiting until the print publication is out."