Abstract Introduction: We aimed to examine how public health policies influenced the dynamics of coronavirus disease 2019 (COVID-19) time-varying reproductive number (R _t ) in South Carolina from February 26, 2020, to January 1, 2021. Methods: COVID-19 case series (March 6, 2020, to January 10, 2021) were shifted by 9 d to approximate the infection date. We analyzed the effects of state and county policies on R _t using EpiEstim. We performed linear regression to evaluate if per-capita cumulative case count varies across counties with different population size. Results: R _t shifted from 2-3 in March to <1 during April and May. R _t rose over the summer and stayed between 1.4 and 0.7. The introduction of statewide mask mandates was associated with a decline in R _t (−15.3%; 95% CrI, −13.6%, −16.8%), and school re-opening, an increase by 12.3% (95% CrI, 10.1%, 14.4%). Less densely populated counties had higher attack rates (P < 0.0001). Conclusions: The R _t dynamics over time indicated that public health interventions substantially slowed COVID-19 transmission in South Carolina, while their relaxation may have promoted further transmission. Policies encouraging people to stay home, such as closing nonessential businesses, were associated with R _t reduction, while policies that encouraged more movement, such as re-opening schools, were associated with R _t increase.