Background: In March 2020, South Africa implemented strict nonpharmaceutical interventions (NPIs) to contain the spread of COVID-19. Over the subsequent 5 months, NPI policies were eased in stages according to a national strategy. COVID-19 spread throughout the country heterogeneously; the disease reached rural areas by July and case numbers peaked from July to August. A second COVID-19 wave began in late 2020. Data on the impact of NPI policies on social and economic well-being and access to health care are limited. Objective: We aimed to determine how rural residents in three South African provinces changed their behaviors during the first COVID-19 epidemic wave. Methods: The South African Population Research Infrastructure Network nodes in the Mpumalanga (Agincourt), KwaZulu-Natal, (Africa Health Research Institute) and Limpopo (Dikgale-Mamabolo-Mothiba) provinces conducted up to 14 rounds of longitudinal telephone surveys among randomly sampled households from rural and periurban surveillance populations every 2-3 weeks. Interviews included questions on the following topics: COVID-19-related knowledge and behaviors, the health and economic impacts of NPIs, and mental health. We analyzed how responses varied based on NPI stringency and household sociodemographics. Results: In total, 5120 households completed 23,095 interviews between April and December 2020. Respondents' self-reported satisfaction with their COVID-19-related knowledge and face mask use rapidly rose to 85% and 95%, respectively, by August. As selected NPIs were eased, the amount of travel increased, economic losses were reduced, and the prevalence of anxiety and depression symptoms fell. When the number of COVID-19 cases spiked at one node in July, the amount of travel dropped rapidly and the rate of missed daily medications doubled. Households where more adults received government-funded old-age pensions reported concerns about economic matters and medication access less often. Conclusions: South Africans complied with stringent, COVID-19-related NPIs despite the threat of substantial social, economic, and health repercussions. Government-supported social welfare programs appeared to buffer interruptions in income and health care access during local outbreaks. Epidemic control policies must be balanced against the broader well-being of people in resource-limited settings and designed with parallel support systems when such policies threaten peoples' income and access to basic services.