Despite having safe and efficacious vaccines against COVID-19, vaccine hesitancy is widespread. Although a trusted source of information, vaccine hesitancy has been reported among healthcare professionals, yet few studies have explored this phenomenon in sub-Saharan Africa. We conducted a cross-sectional survey of healthcare professionals in Sierra Leone from January to March 2022. Measures included sociodemographic/health-related information and COVID-19-related concerns. From the responses, we constructed a hesitancy (VAX) score, with higher scores implying negative attitudes or unwillingness to vaccinate. Multivariate linear regression was used to access factors associated with vaccine hesitancy. Overall, 592 participants submitted responses (67.2% female, mean age 29 years, 5.6% physicians/pharmacists, 44.3% medical students, 29.2% nurses, 20.9% nursing students). The mean VAX score was 43.27 ± 8.77, with 60.1% of respondents classified as vaccine hesitant (>50th percentile) and 11.5% as highly hesitant (>75th percentile). Worries about unforeseen future effects (76.3%), a preference for natural immunity (59.5%), and profiteering/mistrust of health authorities (53.1%) were the most common concerns. Being a medical student (β = 0.105, p = 0.011) and previously refusing a recommended vaccine (β = 0.177, p < 0.001) were predictors of COVID-19 vaccine hesitancy. Our findings call for addressing vaccine hesitancy among healthcare professionals as an essential component of strategies aimed at increasing COVID-19 vaccine uptake in this setting.