Emerging evidence suggests that sex workers face unique and profound risks arising from the COVID-19 pandemic. To illuminate the pandemic’s effects on sex worker health and safety and identify intervention opportunities, from May–August 2020 in-depth interviews were conducted with a purposive sample of 15 sex workers, four service providers and two individuals who were both. Sampled sex workers included eight people of color, eight cisgender women, five cisgender men, three non-binary people, and one transgender woman. Using Conservation of Resources Theory to define impacts on sex worker resources and resulting health and safety implications, a deductive thematic analysis was conducted. Seven resources were threatened due to the pandemic: work opportunity, sex work venues, social support, health services, money, food, and housing. The loss of these resources was exacerbated by stigma – notably sex work criminalization – and significantly undermined health and safety by increasing food and housing instability, increasing risks of violence, and diminishing safer sex negotiation. Six resources were activated in response: social support, digital skills, health knowledge, non-sex work employment, money, and resilience. While social support had numerous benefits, investing digital skills and non-sex work employment were generally of limited impact. The pandemic’s negative health and safety effects were most profound at the intersections of race, gender, class, and migration status. These findings suggest sex workers need urgent and ongoing support, with investments in social support and sex work decriminalization likely to have the greatest effects on health and safety relative to and beyond the COVID-19 pandemic.