The surface chemistry, pendent functional entities, and ease in tunability of various materials play a central role in properly coordinating with enzymes for immobilization purposes. Due to the interplay between the new wave of support matrices and enzymes, the development of robust biocatalytic constructs via protein engineering expands the practical scope and tunable catalysis functions. The concept of stabilization via functional entities manipulation, the surface that comprises functional groups, such as thiol, aldehyde, carboxylic, amine, and epoxy have been the important driving force for immobilizing purposes. Enzyme immobilization using multi-functional supports has become a powerful norm and presents noteworthy characteristics, such as selectivity, specificity, stability, resistivity, induce activity, reaction efficacy, multi-usability, high catalytic turnover, optimal yield, ease in recovery, and cost-effectiveness. There is a plethora of literature on traditional immobilization approaches, e.g., intramolecular chemical (covalent) attachment, adsorption, encapsulation, entrapment, and cross-linking. However, the existing literature is lacking state-of-the-art smart chemistry of immobilization. This review is a focused attempt to cover the literature gap of surface functional entities that interplay between support materials at large and enzyme of interest, in particular, to tailor robust biocatalysts to fulfill the growing and contemporary needs of several industrial sectors.