This paper explores the opportunities and challenges faced by spin-off enterprises operating within multidisciplinary universities in Vietnam. It provides a comprehensive analysis of the current legal framework impacting these enterprises, identifying key regulations and laws essential for their establishment, operation, and growth. The study examines the effectiveness of existing policies and highlights areas requiring improvement to foster a more conducive environment for spin-offs. The paper also presents a set of proposals aimed at enhancing the legal framework, thereby promoting innovation and commercialization of research within academic institutions. Through a detailed review of relevant Vietnamese legal documents, this research aims to offer valuable insights for policymakers, university administrators, and entrepreneurs seeking to optimize the potential of spin-off enterprises in contributing to the knowledge economy.