Background: Studies of positive psychology and emotional well-being have broadened our understanding of mental health. However, mental health research involving autistic adults has been largely deficit-focused. Few studies have examined well-being using established positive psychological frameworks. Methods: This study examined the psychometric characteristics of the PERMA Profiler, a 23-item questionnaire that measures well-being across five subscales (Positive emotion, Engagement, Relationships, Meaning, and Accomplishment), in a sample of 517 autistic adults ages 18–84 years ( M = 39.5, standard deviation [SD] = 13.3). Reliability (internal consistency), structural validity (via confirmatory factor analysis including bifactor modeling), and concurrent validity were examined. Results: The PERMA Profiler mean (SD) well-being score was 5.4 (SD = 1.7), which is notably lower than the mean of 7.0 previously found in nonautistic samples. Subscale scores were highest for Engagement ( M = 6.8; SD = 1.9), followed by Accomplishment ( M = 5.6; SD = 2.2), Relationships ( M = 5.2; SD = 2.6), Meaning ( M = 5.2; SD = 2.7), and Positive emotion ( M = 5.0; SD = 2.4). Factor analyses revealed strong psychometrics (Cronbach's α = 0.93; Comparative Fit Index = 0.94; Tucker–Lewis Index = 0.97; root mean square error of approximation = 0.08; standardized root mean residual = 0.05) and superior fit of the bifactor model, supporting a general factor for conceptualizing well-being as opposed to a five-factor model. PERMA well-being and subscale scores were significantly correlated ( p < 0.001) with mental health conditions and life satisfaction. Conclusion: These findings support use of an adapted version of the PERMA Profiler in mental health research to evaluate well-being among autistic adults. Similar to studies with nonautistic populations, the Engagement measure may not capture the experiences of the autistic population and further refinement is needed. Follow-up research should represent a more diverse autistic population, collaborate with autistic coinvestigators, and explore potential correlates of well-being (such as social stigma) while using the PERMA Profiler.