During DeWine's first term as governor, a shooting in Dayton prompted him to urge the Ohio legislature to enact new gun control measures, such as expanding background checks and harsher penalties for those in possession of unregistered firearms.

In early 2020, DeWine received national attention for his COVID-19 response,[4] ordering the closing of dine-in restaurant service and sporting events and delegating additional resources to elderly care facilities.

He was the initial sponsor of the Drug-Free Century Act in 1999 and was a member of the Gang of 14, a bipartisan group of senators that in 2005 made a compromise on judicial nominees.

[30] As attorney general of Ohio, DeWine sent letters to drugstore chains encouraging them to discontinue the sale of tobacco products.

[37] When he filed the suit, DeWine claimed that the fee was "an unprecedented attempt to destroy the balance of authority between the federal government and the states".

[37] In January 2016, the federal court dismissed DeWine's suit, with U.S. district judge Algenon L. Marbley holding that the Transitional Reinsurance Program did not violate the Constitution.

[39] To that effect, he made it a priority to significantly reduce DNA testing turnaround times in connection with open criminal investigations.

Under his predecessor, DNA testing at the Ohio attorney general's Bureau of Criminal Investigation (BCI) took approximately four months in cases such as murders, rapes, and assaults.

Under the DeWine administration, DNA test results are now returned to local law enforcement in less than a month, leading to faster apprehension of dangerous suspects.

[41] These DNA matches led to the indictments of approximately 700 alleged rapists, many of whom were serial attackers, connected to cases that would never have been solved if not for the DeWine initiative.

By the end of his first year in office, he had worked to close all 12 pill mills in Scioto County, considered by many to have been the national center of the prescription drug crisis.

[48] In October 2017, DeWine announced a 12-pronged plan to combat the opioid epidemic, drawing from his experience breaking up pill mills, prosecuting traffickers, supporting recovery, and advocating the importance of drug-use prevention education.

[50][51] In October 2017, news reports surfaced that Anthony Precourt, the investor-operator of the soccer club Columbus Crew, was exploring the option of moving the team out of state.

[55] As the lawsuit played out, an investor group including Dee and Jimmy Haslam, owners of the Cleveland Browns, and the Columbus-based Edwards family announced in October 2018 they were working out the details of a deal to keep the Crew in Columbus.

He defeated the Democratic nominee, former Consumer Financial Protection Bureau director Richard Cordray in the general election, by a margin of about four percentage points.

[60] On August 6, DeWine proposed to allow judges to confiscate firearms from those deemed potentially dangerous and to provide them with mental health treatment while maintaining their due process rights.

[65] In December 2019, he expressed his support for Ohio allowing cities to ban plastic bags, opposing two bills in the state legislature that would have forbidden it[66] being pushed by fellow Republicans.

[71] On January 27, DeWine signed Senate Bill 7, which gives military members and their spouses better employment opportunities by simplifying the process to transfer their occupational licenses to Ohio.

The cancellation was widely regarded as "radical" at the time[75][76] but was soon seen as less so, with Axios calling DeWine "among the leading governors in the country sounding the alarm about the threat of the coronavirus"[77] and The Washington Post calling his and Acton's response "a national guide to the crisis" and "textbook recommendations",[78] pointing out numerous occasions when moves Ohio made were soon duplicated by other states.

[83] DeWine barred spectators from sporting events; was first in the U.S. to shut down schools throughout his state; and, on the night before it was to take place, postponed Ohio's primary election.

[84] He directed the Ohio Department of Health to order the closing of the state's more than 22,000 food service locations and bars, except for carry-out.

[85] On April 1, the BBC called DeWine "quick to defer to Dr Acton for specific questions on the virus and its spread" during daily news briefings, "reminding Ohioans that the state's decisions are driven by science".

[92][93] In December 2020, DeWine signed a bill that said "fetal remains from surgical abortions in Ohio must be cremated or buried"; failure to do so would be a misdemeanor of the first degree.

[96] Nor has he joined former governor Robert Taft, former attorney general Petro, and former House speaker Householder in calling for an end to Ohio executions.

The same year, DeWine pledged to honor the voters' wishes and support a redistricting process conducted in a bipartisan way, but in 2021 he approved the changes for 2022 onward.

[101] DeWine was one of only two Republican senators to vote against the Protection of Lawful Commerce in Arms Act, which banned lawsuits against gun manufacturers, distributors and dealers for criminal misuse of their products.

[104][105][106] As U.S. senator, DeWine joined a bipartisan effort to lower the national maximum blood-alcohol limit from .1% to .08% and to require reporting of vehicle-related deaths on private property like parking lots and driveways.

"[113][114] In December 2023, he vetoed a bill that would have banned minors from receiving gender-affirming care in Ohio and transgender youth from playing on sports teams that did not match their sex assigned at birth.

[120][121] In February 2024, after backlash from trans people and healthcare providers, DeWine's administration dropped all the proposed rules to restrict treatment for transgender adults.

[122] In November 2024, DeWine signed into law a bill prohibiting students in public schools from using restrooms other than those for the gender they were assigned at birth.