<p>This paper explores the potential of Industrial Symbiosis (IS) for rural Small and Medium Enterprises (SMEs), recognizing their vital economic role despite significant sustainability challenges often worsened by resource limitations and geographical isolation. While IS is known to improve resource efficiency and competitiveness, its application for rural SMEs is under-explored due to unique challenges such as scale, infrastructure deficits, limited access to knowledge/finance, and distinct institutional landscapes. The research uses a mixed-methods approach, combining a systematic literature review with multiple case studies from diverse rural settings, characterized by variable industrial sectors, government support, public actors, facilitator involvement, and geographical proximity. Findings identify critical motivations (e.g., cost reduction), multifaceted benefits (economic, environmental, social), persistent challenges (lack of awareness/trust, financial/technological limits, policy issues), and crucial enabling factors (effective facilitation, targeted policies, anchor firms) for rural SME IS. Cross-case analysis underscores the context-dependent nature of IS but highlights the universal importance of tailored facilitation and supportive governance. The study advances Industrial Symbiosis theory by (i) formally contextualizing IS for rural SMEs, (ii) identifying specific boundary conditions under which IS can emerge and persist in rural settings, and (iii) redefining Sgambaro’s “anatomic variables” as a relational and compensatory framework rather than a fixed set of conditions. Finally, the paper offers actionable proposals for businesses, policymakers, and intermediary organizations, providing guidance on how to design, support, and scale sustainable Industrial Symbiosis ecosystems suited to rural SME contexts.</p>