Healthcare workers have been on the frontline of the battle against COVID-19 disease. However, this has taken a toll on them, resulting in elevated stress and poor mental health. We argue that healthcare workers' stress mindset and resilience could mitigate negative outcomes of COVID-19-related stress by helping them view this stressful situation in a more positive light and appraise it as a challenge rather than a threat. Accordingly, we hypothesized that both a stress-is-enhancing mindset about COVID-19-related stress and resilience would improve healthcare workers' appraisal of their personal resources and increase their challenge appraisals, positively contributing to their mental health. We collected data from 160 healthcare workers and performed structural equation modeling for hypothesis testing. The results indicate that both a stress-is-enhancing mindset about COVID-19-related stress and psychological resilience are indirectly related to better mental well-being and lower health-related anxiety through challenge appraisals. This study contributes to research in mental health by suggesting that protecting and promoting healthcare workers' mental health is possible by empowering them through increasing personal resources such as a positive mindset about stressful situations and resilience.