Objective: This prospective longitudinal study examined whether coronavirus disease 2019 (COVID-19) has led to changes in psychological and spiritual outcomes among adults with chronic disease. Method: Participants (N = 302) were a stratified, nonrandom sample of adults (Mage = 64.46, SD = 10.86, 45.7% female). The sample was representative of the chronically ill, U.S. adult population in gender, race/ethnicity, region, and religious affiliation but older in age and higher in socioeconomic status. Participants completed online-administered measures 1 month before the March 11 pandemic declaration (T1) and then 1 and 3 months after it (T2 and T3). At T1 through T3, they completed measures of depression, anxiety, personal suffering, psychological well-being, trait resilience, optimism, hope, grit, spiritual struggles, spiritual fortitude, and positive religious coping. At T2 and T3, they also completed measures of social support, physical health, resource loss, perceived stress, and COVID-19 fears and exposure. Results: Overall, people did not change substantially in psychological or spiritual outcomes over time. However, trait resilience increased and personal suffering declined. People highest in prepandemic suffering increased in spiritual fortitude. Racial/ethnic minorities increased in religious importance. Roughly half (48.9%) of participants exhibited psychological resilience (no/minimal depression or anxiety symptoms) at both T2 and T3. Perceived stress and psychological resource loss were associated with adverse mental health outcomes, but social support and physical health were not. COVID-19 fears contributed more to mental health than COVID-19 exposure. Conclusions: Even among vulnerable populations such as adults with chronic disease, during pandemic conditions like COVID-19, many people may exhibit—or even increase slightly in—psychological and spiritual resilience.