Promotion of local seafood and related culture has become an important strategy for enhancing economic sustainability of struggling commercial fishing businesses in coastal tourism destinations. Theme-based tourism trails can be catalysts for identifying, recognizing, and sustaining important aspects of culture, heritage, and industry in rural regions. Food-based trails have become a popular strategy for enhancing the economic viability of local food producers while highlighting the authentic qualities of a tourist destination. This study explored potential for development of a seafood-themed trail on the coast of South Carolina (USA) where communities represent varying levels of economic dependence on commercial fishing and tourism. Methods included 31 personal interviews with stakeholders from the seafood and tourism sectors across the region and a follow-up survey (n = 13) and workshop (n = 15) to facilitate input and consensus. Stakeholders supported formation of a coast-wide seafood trail as an education and decision-making tool targeting tourists. They highlighted collaborative capacity for marketing and partnership, diversity of local seafood products and experience, and economic benefits and improved competitive advantage for local businesses as strengths and opportunities. Challenging issues for development and long-term viability included limits to local seafood supply, regional differences in both heritage and seafood products, financial constraints, maintaining interest among stakeholders and visitors, establishing leadership, and defining membership criteria.