Silk fibroin (SF), an organic material obtained from the cocoons of a silkworm Bombyx mori, is used in several applications and has a proven track record in biomedicine owing to its superior compatibility with the human body, superb mechanical characteristics, and its controllable propensity to decay. Due to its robust biocompatibility, less immunogenic, non-toxic, non-carcinogenic, and biodegradable properties, it has been widely used in biological and biomedical fields, including wound healing. The key strategies for building diverse SF-based drug delivery systems are discussed in this review, as well as the most recent ways for developing functionalized SF for controlled or redirected medicines, gene therapy, and wound healing. Understanding the features of SF and the various ways to manipulate its physicochemical and mechanical properties enables the development of more effective drug delivery devices. Drugs are encapsulated in SF-based drug delivery systems to extend their shelf life and control their release, allowing them to travel further across the bloodstream and thus extend their range of operation. Furthermore, due to their tunable properties, SF-based drug delivery systems open up new possibilities for drug delivery, gene therapy, and wound healing.