Existing literature on the effects of psychological resources on health-protective behaviors in coronavirus disease 2019 (COVID-19) and other contexts has focused heavily on cross-sectional relationships. Informed by self-determination theory, the current study aims to overcome this limitation by investigating the cross-sectional and longitudinal relationships among loneliness, purpose in life, and protective behaviors before and during the COVID-19 pandemic in the U.S. older adults. This study uses data from the 2016 and 2020 waves of the Health and Retirement Study, a nationally representative longitudinal panel study of older adults in the United States. The working sample size was 2,649. A path model and a cross-lagged panel model were applied for the analyses. Purpose in life fully mediated the negative impact of loneliness on protective behaviors when measured cross-sectionally. Moreover, prepandemic loneliness was associated with a decrease in purpose in life over time. On the other hand, prepandemic purpose in life was associated with a decrease in loneliness and an increase in protective behaviors over time. Our cross-sectional finding on the mediating role of purpose in life reveals a psychological mechanism useful for future interventions. Furthermore, the longitudinal influence of prepandemic loneliness on purpose in life deserves both scholarly and clinical attention. Most importantly, the longitudinal effects of purpose in life on loneliness and protective behaviors provide guidance for preparing older adults during normal times to cope with loneliness and to comply more with recommended measures during future health crises (such as the COVID-19 pandemic).