The COVID-19 pandemic has significantly influenced substance prevention work, exacerbating existing challenges and providing new opportunities for community-based substance prevention networks (CSPNs). CSPNs are interorganizational networks that include various providers, such as nonprofits and government agencies, that collaborate to provide substance prevention services and are embedded in local communities. This study analyzes the post-pandemic adaptation of a CSPN in the United States. Through qualitative thematic analysis of interview data with network leaders, this study identifies two primary challenges: resource constraints and engagement obstacles and two primary opportunities: innovation in service delivery and data importance. The findings affirm what is known about the barriers to substance prevention and point to a novel shift in community-based substance prevention work. Particularly, CSPNs are adopting harm-reduction tactics and expanding digital outreach to support clients. As CSPNs continue to emerge, this research provides insight into the evolving landscape of substance prevention work and the critical role of community-based networks. The findings in this study offer practical implications for enhancing CSPN effectiveness and resilience in substance prevention.