Aim: This study aims to assess how optimism, social support, and perceived susceptibility are associated with depressive symptoms and health-related quality of life among elderly patients during the COVID-19 pandemic in Israel. Methods: In a cross-sectional study, 256 participants age 60 through 95 completed the following self-administered questionnaires: Perceived Susceptibility, Life Orientation Test (LOT-R), Multidimensional Scale of Perceived Social Support (MSPSS), Symptoms of Depression (CES-D) and health-related quality of life (SF-12v2 Health Survey). Data were collected from June to July 2020, 3 months after the COVID-19 state of emergency was declared in Israel. Participants were interviewed by family medicine residents via telephone. Statistical analyses included Pearson correlations, t-tests between groups, regression analyses, and Hayes’ PROCESS to analyze a moderated mediation model. Results: Of the elderly participants, 37.5% were classified as having depression. Optimism, social support and health-related quality of life were positively associated. Higher optimism and social support were related to lower perceived susceptibility and lower depression. Results of a multivariate regression explained 29% of the variance in depression and 19% of the variance in health-related quality of life. The relationships assessed by 4 Process models were significant, such that higher optimism and social support were related to lower perceived susceptibility, which in turn was related to higher depression and lower health-related quality of life. Conclusions: Optimism and social support may be effective in coping with challenges and buffering depression. Perceived susceptibility may mediate the association of optimism and social support with higher depression and lower health-related quality of life. The conclusions of this study underscore the need to treat depression among older adults during this period. Hence, healthcare providers should also support elderly patients living at home. In giving this type of help, healthcare providers should strive to increase social support and optimism among older adults.