Biomaterials are of significant importance in biomedical applications as these biological macromolecules have moderately replaced classical tissue grafting techniques owing to its beneficial properties. Despite of its favourable advantages, poor mechanical and degradative properties of biomaterials are of great concern. To this regard, crosslinkers have emerged as a smart and promising tool to augment the biological functionality of biopolymers. Different crosslinkers have been extensively used in past decades to develop bone substitutes, but the implications of toxic response and adverse reactions are truly precarious after implantation. Traditional crosslinker like glutaraldehyde has been widely used in numerous bio-implants but the potential toxicity is largely being debated with many disproving views. As alternative, green chemicals, enzymatic and non-enzymatic chemicals, bi-functional epoxies, zero-length crosslinkers and physical crosslinkers have been introduced to achieve the desired properties of a bone substitute. In this review, systematic literature search was performed on PubMed database to identify the most commonly used crosslinkers for developing promising bone like materials. The relevant articles were identified, analysed and reviewed in this paper giving due importance to different crosslinking methodologies and comparing their effectiveness and efficacy in regard to material composition, scaffold production, crosslinker dosage, toxicity and immunogenicity. This review summarizes the recent developments in crosslinking mechanism with an emphasis placed on their ability to link proteins through bonding reactions. Finally, this study also covers the convergent and divergent methodologies of crosslinking strategies also giving special importance in retrieving the current limitations and future opportunities of crosslinking modalities in bone tissue engineering.