BACKGROUND/OBJECTIVES: Few studies have rigorously examined the magnitude of changes in well‐being after a transition into sustained and substantial caregiving, especially in population‐based studies, compared with matched noncaregiving controls. DESIGN: We identified individuals from a national epidemiological investigation who transitioned into caregiving over a 10‐ to 13‐year follow‐up and provided continuous in‐home care for at least 18 months and at least 5 hours per week. Individuals who did not become caregivers were individually matched with caregivers on age, sex, race, education, marital status, self‐rated health, and history of cardiovascular disease at baseline. Both groups were assessed at baseline and follow‐up. SETTING: REasons for Geographic And Racial Differences in Stroke study. PARTICIPANTS: A total of 251 incident caregivers and 251 matched controls. MEASUREMENTS: Perceived Stress Scale (PSS), 10‐Item Center for Epidemiological Studies‐Depression (CES‐D), and 12‐item Short‐Form Health Survey quality‐of‐life mental (MCS) and physical (PCS) component scores. RESULTS: Caregivers showed significantly greater worsening in PSS, CES‐D, and MCS, with standardized effect sizes ranging from 0.676 to 0.796 compared with changes in noncaregivers. A significant but smaller effect size was found for worsening PCS in caregivers (0.242). Taking on sustained caregiving was associated with almost a tripling of increased risk of transitioning to clinically significant depressive symptoms at follow‐up. Effects were not moderated by race, sex, or relationship to care recipient, but younger caregivers showed greater increases in CES‐D than older caregivers. CONCLUSION: Persons who began substantial, sustained family caregiving had marked worsening of psychological well‐being, and relatively smaller worsening of self‐reported physical health, compared with carefully matched noncaregivers. Previous estimates of effect sizes on caregiver well‐being have had serious limitations due to use of convenience sampling and cross‐sectional comparisons. Researchers, public policy makers, and clinicians should note these strong effects, and caregiver assessment and service provision for psychological well‐being deserve increased priority.