Growth mindset, the belief that abilities and attributes are changeable, has been implicated in better mental health and health behaviors and may be especially critical during challenging life events. One goal of this prospective longitudinal study was to investigate the role of growth mindset in adults’ mental health (i.e., depression, well-being, and adjustment of daily routines) over two years of the COVID-19 pandemic. We also examined this relationship in older adults who had participated in a prior learning intervention, including growth mindset training (compared with those who had not). Adults ages 19 to 89 from ethnically diverse backgrounds in Southern California (n = 454) were surveyed at three timepoints between June 2020 and September 2022. In Study 1, focusing on this wide age range (n = 393), we found that a growth mindset was associated with lower levels of depression and higher levels of well-being and adjustment, after accounting for various sociodemographic factors. Study 2, which focused on older adults (n = 174), largely replicated the findings from Study 1. Furthermore, the conducive effect of a growth mindset on well-being was marginally greater among those who had participated in the intervention, and those who had participated in the intervention showed an increase in well-being over time, while well-being scores decreased in the control group. Together, our findings suggest that a growth mindset may be an important protective factor for mental health during challenging times.