Purpose To assess mental well-being (MW), self-efficacy (SE), and their predictors among healthcare workers (HCWs) in Saudi Arabia during the COVID-19 pandemic. Methods Analytical cross-sectional study recruited 1046 HCWs by cluster random sampling technique. Socio-demographic, health, and occupational characteristics were collected for all participants. The WHO five Well-Being Index (WHO-5) and General Self-Efficacy Scale (GSES) were used to assess MW and SE of the participants, respectively. The binary logistic regression model was fit to the dependent (outcomes), namely mental well-being and self-efficacy, and independent other variables (predictors). Results Out of all participants (n=1046), 27.2% had negative MW scores, and 36.6% had low SE scores. The mean scores of both MW and SE were in the normal levels (16.7±5.90 and 31.5±6.63 out of 25 and 40, respectively). Younger and older ages, irregular exercise, nursing professions, history of anxiety and/or depression, lesser years of experience, and longer daily working hours were found to be the main predictors of negative MW and low SE, among study participants. Conclusion Mental well-being (MW) and self-efficacy (SE) of the HCWs in Saudi Arabia are satisfactory but attention should be paid towards supporting the vulnerable groups for promoting the resilience of HCWs during the battle against the current pandemic.