As of October 7, 2021[update], the Pennsylvania Department of Health has confirmed 1,464,264 cumulative cases and 29,814 deaths in the state.

Initially, Governor Wolf implemented social distancing measures in Bucks, Chester, Delaware, and Montgomery counties in the Philadelphia suburbs along with Allegheny County in the Pittsburgh area, which urged non-essential businesses operations and services to close, such as malls, movie theaters, and casinos.

On March 16, 2020, the social distancing measures were extended to the entire state, while Philadelphia Mayor Jim Kenney ordered nonessential businesses and city government to close for two weeks.

[163] On March 17, 2020, all Fine Wine & Good Spirits stores across the state closed at the end of the business day.

[15] SEPTA Regional Rail trains in the Philadelphia area began operating on an enhanced Saturday schedule for two weeks due to reduced ridership and staffing.

[165] On March 22, 2020, Philadelphia Mayor Jim Kenney issued a stay-at-home order for the city, set to take effect the following day at 8:00 am.

As a result, restaurants, small businesses, theaters, galleries, and performance spaces were temporarily shuttered to stem the spread of the virus.

[174] In an effort to aid small and locally owned businesses, Pennsylvania legislators created funds for proprietors.

[177] In October 2020, lawmakers introduced "Save the Stages" legislation (PA House Bill 2894)[178] designed to provide $200 million of the CARES Act to performance venues or associated businesses impacted by COVID-19.

[120] In January 2022, many schools temporarily switched to virtual learning due to an increase in COVID-19 cases among students and staff caused by the SARS-CoV-2 Omicron variant.

[183] In March 2020, many colleges and universities throughout Pennsylvania suspended in-person classes and moved to virtual learning in wake of the COVID-19 pandemic.

Despite funding from the CARES ACT, many districts had to increase taxes, make budgets, or draw from reserves, or some combination of the three strategies.

[186][187] In March 2020 with the passage of 2020 Act 12, the primary election was postponed to June 2, 2020, to allow for mail in ballots and pre-canvassing.

[195][196] Following legal challenge, the Pennsylvania Supreme Court upheld the extended period of receipt of mail in ballots.

Major League Baseball cancelled the remainder of spring training on that date, and on March 16, 2020, they announced that the season will be postponed indefinitely, after the recommendations from the CDC to restrict events of more than 50 people for the next eight weeks, affecting the Philadelphia Phillies and Pittsburgh Pirates.

[201] In the National Hockey League, the season was suspended for an indefinite amount of time, affecting the Pittsburgh Penguins and Philadelphia Flyers.

[204] The 76ers completed the regular season after the restart and ended up as the 6 seed in the East; the 76ers were swept in the first round of the playoffs by the Boston Celtics.

[206] On July 27, 2020, National Football League preseason games, which usually take place in August, were cancelled by NFL Commissioner Roger Goodell due to the COVID-19 pandemic, affecting the Philadelphia Eagles and the Pittsburgh Steelers.

[208][209] After the city of Philadelphia announced restrictions on November 16, 2020, due to a rise in cases, the Eagles were again not allowed to have any fans at games.

[210] The state originally planned to allow a limited number of spectators for the Steelers home playoff game(s).

[214] On August 11, the Big Ten Conference, which includes the Penn State Nittany Lions, postponed their fall 2020 sports seasons.

[215] The Army–Navy Game, which was scheduled to take place at Lincoln Financial Field in Philadelphia on December 12, 2020, was moved to Michie Stadium on the grounds of the United States Military Academy in West Point, New York due to attendance limits on outdoor events imposed by the state.

Among other challenges, Wolf has cited a lack of supply from federal agencies in preventing quicker and more widespread inoculation.