Businesses are facing increasing pressure from multiple stakeholders to integrate sustainability into their practices and business models. Although Small and Medium-sized Enterprises (SMEs) represent at least 90% of businesses worldwide and contribute approximately 60% of environmental impacts, assessing and improving their sustainability performance is not a priority for them. SMEs can address sustainability issues through the application of the different Life Cycle Assessment (LCA) approaches. LCA focuses solely on the environment; however, other forms, such as social, costing, sustainability, and organizational LCA, enable practitioners to assess impacts across the entire life cycle of the studied system, each with different scopes and approaches. However, LCA remains in the domain of large companies. This article aims to identify the main barriers and enablers of LCA in SMEs for wider use as a tool to improve sustainability performance. Through a systematic review of the scientific literature on LCA among SMEs applying the Standardized Technique for Assessing and Reporting Reviews of LCA data, a sample of 61 articles provides a 20-year history. Our results characterize the application of LCA in SMEs through six main aspects. Our main conclusions identify three main barriers to the application of LCA among SMEs: lack of trained personnel, lack of data, and high costs. To overcome these barriers, we found that narrowing down the scope using simplified methods in clusters can increase the use of LCA among SMEs. A simplified SME cluster-elaborated LCA can be used to qualitatively identify sustainability hotspots, develop suitable strategies to improve sustainability performance, and respond to market requests.