The 2020-2021 National Football League (NFL) season had some games with fans and others without. Thus, the exposed group (ie, games with fans) and the unexposed group (games without fans) could be examined to better understand the association between fan attendance and local incidence of COVID-19. To assess whether NFL football games with varying degrees of in-person attendance were associated with increased COVID-19 cases in the counties where the games were held, as well as in contiguous counties, compared with games without in-person attendance for 7-, 14-, and 21-day follow-ups. This cross-sectional study used data for all 32 NFL teams across the entirety of the 2020-2021 season. Separate daily time-series of COVID-19 total cases and case rates were generated using 7-, 14-, and 21-day simple moving averages for every team and were plotted against the actuals to detect potential spikes (outliers) in incidence levels following games for the county in which games took place, contiguous counties, and a combination. Outliers flagged in the period following games were recorded. Poisson exact tests were evaluated for differences in spike incidence as well across games with different rates of attendance. The data were analyzed between February 2021 and March 2021. Games with fan attendance vs games with no fan attendance, as well as the number of fans in attendance for games with fans. The main outcome was estimation of COVID-19 cases and rates at the county and contiguous county level at 7-, 14-, and 21-day intervals for in-person attended games and non-fan attended games, which was further investigated by stratifying by the number of persons in fan-attended games. This included a total of 269 NFL game dates. Of these games, 117 were assigned to an exposed group (fans attended), and the remaining 152 games comprised the unexposed group (unattended). Fan attendance ranged from 748 to 31 700 persons. Fan attendance was associated with episodic spikes in COVID-19 cases and rates in the 14-day window for the in-county (cases: rate ratio [RR], 1.36; 95% CI, 1.00-1.87), contiguous counties (cases: RR, 1.31; 95% CI, 1.00-1.72; rates: RR, 1.41; 95% CI, 1.13-1.76), and pooled counties groups (cases: RR, 1.34; 95% CI, 1.01-1.79; rates: RR, 1.72; 95% CI, 1.29-2.28) as well as for the 21-day window in-county (cases: RR, 1.49; 95% CI, 1.21-1.83; rates: RR, 1.50; 95% CI, 1.26-1.78), in contiguous counties(cases: RR, 1.37; 95% CI, 1.14-1.65; rates: RR, 1.45; 95% CI, 1.24-1.71), and pooled counties groups (cases: RR, 1.41; 95% CI, 1.11-1.79; rates: RR, 1.70; 95% CI, 1.35-2.15). Games with fewer than 5000 fans were not associated with any spikes, but in counties where teams had 20 000 fans in attendance, there were 2.23 times the rate of spikes in COVID-19 (95% CI, 1.53 to ∞). In this cross-sectional study of the presence of fans at NFL home games during the 2020-2021 season, results indicated that fan attendance was associated with increased levels of COVID-19 in the counties in which the venues are nested within, as well as in surrounding counties. The spikes in COVID-19 for crowds of over 20 000 people suggest that large events should be handled with extreme caution during public health event(s) where vaccines, on-site testing, and various countermeasures are not readily available to the public.