Genipin is a naturally occurring nontoxic cross-linker, which has been widely used for drug delivery due to its excellent biocompatibility, admirable biodegradability and stable cross-linked attributes. These advantages led to its extensive application in the fabrication of hydrogels for drug delivery. This review describes the physicochemical characteristics and pharmacological activities of genipin and attempts to elucidate the detailed mechanisms of the cross-linking reaction between genipin and biomaterials. The current article entails a general review of the different biomaterials cross-linked by genipin: chitosan and its derivatives, collagen, gelatin, etc. The genipin-cross-linked hydrogels for various pharmaceutical applications, including ocular drug delivery, buccal drug delivery, oral drug delivery, anti-inflammatory drug delivery, and antibiotic and antifungal drug delivery, are reported. Finally, the future research directions and challenges of genipin-cross-linked hydrogels for pharmaceutical applications are also discussed in this review.