AbstractIntroductionStress and adversity during childhood, adolescence, and adulthood could impact the present and future health and well‐being of people with multiple sclerosis (PwMS); however, a lifespan approach and nuanced stressor data are scarce in this nascent area of research. Our aim was to examine relationships among comprehensively measured lifetime stressors and two self‐reported MS outcomes: (1) disability and (2) relapse burden changes since COVID‐19 onset.MethodsCross‐sectional data were collected from a nationally distributed survey of U.S.‐based adults with MS. Hierarchical block regressions were used to sequentially evaluate contributions to both outcomes independently. Likelihood ratio (LR) tests and Akaike information criterion (AIC) were used to evaluate additional predictive variance and model fit.ResultsA total of 713 participants informed either outcome. Most respondents (84%) were female, 79% had relapsing remitting multiple sclerosis (MS), and mean (SD) age was 49 (12.7) years. Childhood (R2= .261,p< .001; AIC = 1063, LRp< .05) and adulthood stressors (R2= .2725,p< .001, AIC = 1051, LRp< .001) contributed significantly to disability, above and beyond prior nested models. Only adulthood stressors (R2= .0534,p< .001; AIC = 1572, LRp< .01) significantly contributed above the nested model for relapse burden changes since COVID‐19.ConclusionsStressors across the lifespan are commonly reported in PwMS and could contribute to disease burden. Incorporating this perspective into the “lived experience with MS” could facilitate personalized health care by addressing key stress‐related exposures and inform intervention research to improve well‐being.