Chemoenzymatic synthesis is an emerging and versatile approach that integrates the selectivity of enzymatic reactions with the flexibility of chemical synthesis to develop complex, chiral, and pharmacologically optimized drug molecules. This strategy plays a pivotal role in drug design and development by enabling the synthesis of compounds with improved efficacy, bioavailability, and safety. Enzymes such as oxidoreductases, lipases, and cytochrome P450s are widely used to catalyse highly specific reactions, facilitating the generation of enantiomerically pure compounds and functionalized intermediates essential for late-stage modification. Chemoenzymatic methods are instrumental in studying drug metabolism, particularly in generating metabolites that mimic in vivo transformations. This supports pharmacokinetic, toxicological, and structure–activity relationship studies, contributing to a deeper understanding of drug action and resistance mechanisms. Hybrid drug design, another advanced approach discussed in this chapter, involves the rational fusion of two or more pharmacophores into a single molecule to achieve multitarget activity, reduce resistance, and improve treatment outcomes especially in the context of cancer, malaria, and microbial infections. Furthermore, enzymatic derivatization of natural products enables the modification of alkaloids, terpenoids, and other scaffolds to enhance solubility, potency, and metabolic stability. These innovations are aligned with the principles of green and sustainable chemistry, promoting safer, cleaner, and more efficient drug manufacturing. As regulatory standards tighten and the demand for better therapeutics grows, chemoenzymatic and hybrid approaches will continue to play a transformative role in pharmacology and pharmaceutical sciences.