Mucoadhesive drug-delivery systems (MDDS) are designed to adhere to mucosal tissues, enhancing both local and systemic drug absorption. The addition of bioenhancers agents that improve membrane permeability, inhibit metabolic degradation, or modulate efflux transporters addresses issues of low mucosal permeability and first-pass metabolism affecting many therapeutic molecules, like peptides and poorly soluble drugs. This review examines the fundamentals of mucoadhesion, focusing on polymer–mucin interactions and mechanical retention forces, while categorizing bioenhancers into plant-derived molecules, surfactants, medium-chain fatty acids, bile salts, and synthetic promoters. It discusses their mechanisms, formulation strategies (such as buccal films and hydrogels), and co-loading principles that enhance absorption. Evaluation techniques, including in vitro and in vivo studies, are outlined to support systematic development. Case studies illustrate the effectiveness of bioenhanced systems, such as piperine for rifampicin delivery and medium-chain fatty acids. Key safety and regulatory considerations related to mucosal irritation and the acceptance of bioenhancers are also addressed. Lastly, emerging trends in mucoadhesive technologies suggest pathways for safer and more effective drug delivery.