OBJECTIVE: As the COVID-19 pandemic presented new challenges for businesses and worker safety and health, an interdisciplinary team launched the COVID-19 Worksite Impact Survey to assess COVID-19-related impacts and responses at small and medium businesses in 10 North Carolina counties. METHODS: We collected data from October 2 to December 1, 2020, and analyzed survey results to evaluate businesses' operational changes, concerns, needs, pandemic preparedness, workplace health promotion programming, and infection control practices. RESULTS: Most businesses, including essential ones, were inadequately prepared for the pandemic and did not implement the most effective COVID-19 infection control practices. Larger businesses and those with existing preparedness practices or health promotion programs were more likely to implement effective measures. CONCLUSIONS: We should be acting now to improve small and medium businesses' preparedness for future public health crises.