<p>In medicinal chemistry, biocatalysis has become an essential tool, providing effective and sustainable alternatives to conventional chemical catalysis. Enzymes provide high chemo-, regio-, and stereoselectivity under mild, environmentally friendly conditions, reducing the need for protecting groups and leading to very little waste. The discovery of new enzymes, such as NADPH-dependent <i>Rhodococcus pyridinivorans and Yarrowia lipolytica</i> carbonyl reductases, that use effective cofactor regeneration systems to synthesize valuable statin precursors with high yield and enantiopurity has recently expanded due to genome mining. The different techniques used in Enzyme engineering techniques, which include direct evolution and computational design, have helped expand substrate scope, which enhances stability in aqueous and organic media, and this enabled integration into multi-step cascades. These innovations address long-standing challenges in the scalability, tolerance, and availability of enzymes, bringing biocatalysis into both early-stage drug discovery and large-scale active pharmaceutical ingredient (API) manufacturing. Beyond reductions and oxidations, new enzymatic strategies now enable the selective formation of C–C bonds, halogenation, and transformations, which align with the principles of green chemistry. This review highlights the latest developments in sustainable enzymatic reactions for drug synthesis, emphasizing practical applications, examples of API production as case studies, and prospects for biocatalysis integration into industrial medicinal chemistry.</p> Graphical abstract <p></p>