Suffering has been a topic of considerable discussion in the fields of medicine and palliative care, yet few studies have reported causal evidence linking the experience of suffering to health and well-being. In this three-wave prospective cohort study, we explore the potential psychological implications of suffering during the COVID-19 pandemic by examining relations among suffering, mental health, and psychological well-being in a sample of U.S. adults living with chronic health conditions. We analyzed data from n = 184 participants who completed assessments one month before the SARS-CoV-2 outbreak was declared a pandemic by the World Health Organization (February 2020) and then two months (April 2020) and four months later (May/June 2020). Analyses controlled for a range of factors, including sociodemographic characteristics, physical health, religious/spiritual factors, psychological characteristics, and prior values of the predictor and each of the outcomes assessed one month before the COVID-19 pandemic. Results of the primary analysis indicated that greater overall suffering assessed one month into the COVID-19 pandemic was associated with lower psychological well-being (β = -.17, 95% CI: -.29, -.05) and higher levels of anxiety (β = .27, 95% CI: .13, .41) and depression (β = .16, 95% CI: .03, .29) two months later. In a secondary analysis that explored anxiety, depression, and psychological well-being as candidate antecedents of suffering, depression assessed one month into the COVID-19 pandemic was most strongly associated with worse overall suffering two months later. We highlight the implications of the findings for high-risk populations who are suffering amidst the challenges of the COVID-19 pandemic. Potential benefits of both integrating assessments of suffering into screening procedures and addressing experiences of suffering in mental health service settings are discussed.