Occupational therapy practitioners need evidence to support interventions that promote subjective well-being among autistic people and their families through optimal engagement and participation in occupations. These Practice Guidelines are informed by systematic reviews to expand knowledge of interventions that promote access, inclusion, engagement, and optimal participation in occupations that are meaningful to autistic people. Our intent was to foster occupational therapy practitioners' clinical decision-making and reasoning when working with autistic people and their care partners. These Practice Guidelines were developed on the basis of four systematic reviews, supporting evidence and literature, along with continued revisions and integration through an iterative and collaborative process. A total of 98 articles were included in the systematic reviews, which are the foundation for practice recommendations in these guidelines. Forty-eight of the systematic review articles were used to inform the clinical recommendations included in these Practice Guidelines. Strong to moderate evidence indicates the need for multidisciplinary, goal-oriented interventions to support autistic people in different contexts. Although there is only emerging evidence in the inclusion of autistic people's strengths, interests, and perspectives to guide occupational therapy interventions, such practices can enhance the delivery of neurodiversity-affirming and trauma-informed practices. In addition, evidence is needed to support participation in activities of daily living (ADLs) for autistic youths. We recommend the use of strengths-based language to describe autistic people and the use of environmental adaptations, care partner education, and coaching to enhance occupational therapy service delivery. Plain-Language Summary: The literature is sparse regarding neurodiversity-affirming and trauma-informed practices for autistic youths, as well as for participation in activities of daily living (ADLs). These Practice Guidelines provide new information on positive mental health development; self-determination; ADLs, instrumental ADLs, play, and leisure occupations for children, adolescents, and adults; person-centered planning for adolescents and adults; and rest and sleep. Information on health management is also provided. Positionality Statement: This article uses the identity-first language autistic people. This nonableist language describes their strengths and abilities and is a conscious decision. This language is favored by autistic communities and self-advocates and has been adopted by health care professionals and researchers (Bottema-Beutel etal., 2021; Kenny etal., 2016). However, we respect the use of person-first language and have made a conscious decision to include research articles that have used this language.