Background: Participation in meaningful activities is important for quality of life among youth with disabilities; yet participation is often restricted during adverse times. This study aimed to explore the effectiveness of the Pathways and Resources for Engagement and Participation (PREP) intervention among ultra-Orthodox Jewish Israeli youth with disabilities during the COVID-19 pandemic. Methods: A 20-week single-subject research design with multiple baselines measuring participation goals/activities was employed with two youths (15 and 19 years old) combining quantitative and qualitative descriptive data. Changes in participation levels were measured biweekly using the Canadian Occupational Performance Measure; COPM; participation patterns were measured using the Participation and Environment Measure—Children and Youth; PEM-CY pre- and post-intervention; parents’ satisfaction was measured using the Client Satisfaction Questionnaire, CSQ-8. Semi-structured interviews were conducted post-intervention. Results: Both participants significantly improved participation in all selected goals and participation patterns, and were highly satisfied with the intervention. The interviews revealed additional information on personal and environmental barriers, factors supporting intervention, and intervention effects. Conclusions: The results indicated that an environment-centered and family-centered approach can potentially improve the participation of youths with disabilities within their unique socio-cultural context, during adverse times. Flexibility, creativity, and collaboration with others also contributed to intervention success.