Skin and Soft Tissue Infections (SSTIs) are common bacterial infections. We hypothesized that due to the COVID-19 pandemic, SSTI rates would significantly decrease due to directives to avoid unneeded care and attenuated SSTIs risk behaviours. We retrospectively examined all patients with an ICD-10 diagnosis code in the Los Angeles County Department of Health Services, the second largest U.S. safety net healthcare system between 16 March 2017 and 15 March 2022. We then compared pre-pandemic with intra-pandemic SSTI rates using an interrupted time series analysis. We found 72,118 SSTIs, 46,206 during the pre-pandemic period and 25,912 during the intra-pandemic period. Pre-pandemic SSTI rate was significantly higher than the intra-pandemic rate (3.27 vs. 2.31 cases per 1,000 empanelled patient-months, P < 0.0001). The monthly SSTI cases decreased by 1.19 SSTIs/1,000 empanelled patient-months between the pre- and intra-pandemic periods (P = 0.0003). SSTI subgroups (inpatient, observation unit, emergency department, and outpatient clinics), all had significant SSTI decreases between the two time periods (P < 0.05) except for observation unit (P = 0.50). Compared to the pre-COVID-19 pandemic period, medically attended SSTI rates in our large U.S. safety net healthcare system significantly decreased by nearly 30%. Whether findings reflect true SSTI decreases or decreased health system utilization for SSTIs requires further examination.