Mastriano, who was endorsed by Donald Trump (between presidencies), won the Republican nomination with 44% of the vote over former congressman Lou Barletta and former U.S. attorney William McSwain.

Although the election was expected to be competitive due to Pennsylvania's reputation as a swing state, Mastriano had trouble fundraising, made few media appearances, committed multiple gaffes, was accused of antisemitism against Shapiro, and generated controversy from his far-right positions.

[citation needed] According to Ron Brownstein of CNN in 2023, Shapiro won independent voters by 31 percentage points, which contributed to Mastriano's defeat.

The New York Times reported in mid-June that Mastriano had been aided in the primary by the Pennsylvania Democratic Party and Shapiro's campaign with an ad equating him to Trump.

Shapiro defended the move, saying the ad demonstrated the contrast between him and Mastriano as part of the general election campaign.

On criminal justice issues, Shapiro promised to sign a bill abolishing the death penalty having previously supported it, but also faced criticism from some left-wing voters for adopting a "tough on crime" image.

[198] State Senator Doug Mastriano positioned himself as a staunch ally of former president Donald Trump, promoting conspiracy theories about the 2020 election, defense of Confederate monuments,[199] arming school teachers with firearms,[200] and disobeying COVID-19 safety protocols.

[203] In addition, Mastriano did not release his first general election ads until October, while the more well-funded Shapiro had already spent $18.6 million in television broadcasting by that time.

[204] These factors, combined with Mastriano's refusal to talk to major media outlets and decision to ban journalists from campaign rallies, severely limited his voter outreach.

Mastriano also carried Lancaster, including the counties contained either fully or partially within his State Senate district, namely Adams, Franklin and York.

According to Ron Brownstein of CNN in 2023, Shapiro won independent voters by double-digit margins, which contributed to Mastriano's defeat.