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Simple Summary: The COVID-19 pandemic may have impacted cancer mortality rates by disrupting patient health behaviors and access to cancer care, as well as being directly affected by infection with SARS-CoV-2. There is limited population-based research that investigates the impact of the COVID-19 pandemic on cancer mortality in the United States. The aim of our retrospective study was to quantify the change in cancer mortality from before the COVID-19 pandemic to during the COVID-19 pandemic in Pennsylvania. We found that mortality rates did not continue their previous downward trajectory and twenty-six counties had an increase in the rate in 2020. The 2015–2019 rates were positively associated with the 2020 rates, and the impact of sociodemographic and geographic factors on the 2020 rates varied by county. Our findings suggest a negative effect of the pandemic on cancer mortality in Pennsylvania and had a varied effect on its counties. Future research could confirm our findings, and if confirmed, may inform cancer research, care, and outreach. Background. We sought to quantify the impact of the COVID-19 pandemic on cancer mortality and identify associated factors in Pennsylvania. Methods. The retrospective study analyzed cross-sectional cancer mortality data from CDC WONDER for 2015 through 2020 for Pennsylvania and its 67 counties. The spatial distributions of 2019, 2020, and percentage change in age-adjusted mortality rates by county were analyzed via choropleth maps and spatial autocorrelation. A Wilcoxon Signed Rank Test was used to analyze whether the rates differed between 2019 and 2020. Quasi-Poisson and geographically weighted regression at the county level were used to assess the association between the 2019 rates, sex (percent female), race (percent non-White), ethnicity (percent Hispanic/Latino), rural–urban continuum codes, and socioeconomic status with the 2020 rates. Results. At the state level, the rate in 2020 did not reflect the declining annual trend (−2.7 per 100,000) in the rate since 2015. Twenty-six counties had an increase in the rate in 2020. Of the factors examined, the 2019 rates were positively associated with the 2020 rates, and the impact of sociodemographic and geographic factors on the 2020 rates varied by county. Conclusions. In Pennsylvania, the 2020 cancer mortality rates did not decline as much as reported before the COVID-19 pandemic. The top five cancer types by rate were the same type for 2019 and 2020. Future cancer control efforts may need to address the impact of the COVID-19 pandemic on trends and geospatial distribution in cancer mortality. [ABSTRACT FROM AUTHOR]