Background: The Gaza Strip, like other settings of complex humanitarian emergencies, faces immense challenges in vaccinating its population against COVID-19. This study was conducted in October 2021 and aimed to estimate coverage of COVID-19 vaccination, levels of vaccine hesitancy, and associations with risk factors among the adult population and healthcare workers (HCWs). Methods: The study used a mixed methods design comprised of a cross-sectional survey of adults, purposive survey of HCWs, and qualitative discussions with key informants and community members. Quantitative data was summarized as univariable descriptive statistics with unweighted and weighted point estimates. Logistic regression was used to evaluate associations of risk factors with vaccination status and vaccine hesitancy.Results: A total of 1,075 individuals were reached in the survey, of whom 906 were community members. Population-weighted vaccine coverage was estimated to be 49.08% (95% CI: 43.10-55.08). 89.35% of HCWs were vaccinated. Population-weighted vaccine hesitancy was estimated to be 34.08% (95% CI: 28.14-40.56) among both vaccinated and unvaccinated respondents, and 67.24% (95% CI: 49.04-81.41) among the unvaccinated. In logistic regression vaccination was independently associated with male sex (aOR 1.88, 95% CI: 1.20-2.95), older age (40 or more years old) (aOR: 1.92, 95% CI: 1.73-2.13), higher education (aOR 2.19, 95% CI: 1.51-3.17), and confidence in the safety of the vaccine (aOR 13.8, 95% CI: 10.1-18.8). Risk factors for hesitancy were similar, however hesitant individuals were more likely to obtain vaccine information from family members (aOR: 1.20, 95% CI: 1.00-1.67) and less likely to trust healthcare providers (aOR: 0.58, 95% CI: 0.49-0.68). Qualitative interviews corroborated the survey results, although skepticism expressed by HCWs interviewed raises the possibility of hidden hesitancy.Conclusions: The continued emergence of SARS-CoV-2 variants reinforces the importance of achieving high levels of vaccination coverage globally – a uniquely challenging objective in Gaza. This study estimated half of Gaza’s adult population received at least one dose of any COVID-19 vaccine by October 2021, and the majority of unvaccinated individuals were hesitant. Disparities in vaccination across the territory’s demographic groups underscores the need for targeted outreach to these populations and messaging through community-based channels to permeate social networks of the unvaccinated.