Abstract Oxazine derivatives are an important class of heterocyclic compounds that have gained significant attention due to their diverse biological and pharmacological activities. Recent studies (2024–2025) highlight their potential in medicinal chemistry, particularly as antimicrobial, anticancer, anti-inflammatory, and antioxidant agents. Their structural versatility and broad spectrum of activity make them promising scaffolds for the development of new therapeutic compounds. Advances in synthetic methodo logies have improved the accessibility and efficiency of oxazine derivatives. Modern approaches such as green chemistry techniques, one-pot multicomponent reactions, and nanocatalysis enable the synthesis of diverse oxazine frameworks under mild and eco-friendly conditions. These methods not only enhance yields and selectivity but also reduce environmental impact, supporting sustainable chemical practices. In addition, structure–activity relationship (SAR) studies have provided valuable insights into the role of different substituents in influencing biological activity. Variations in electronic and steric properties significantly affect the pharmacological behavior of these compounds, aiding in the rational design of more potent and selective molecules. This review summarizes recent developments in the synthesis, biological evaluation, and SAR of oxazine derivatives, emphasizing their importance as versatile scaffolds for future drug discovery and the design of improved therapeutic agents.