The high solubility of gelatin in neutral, basic, and acidic biofluids may not promote a controlled drug delivery as a drug carrier. The present study reports the modification of the solubility and swellability of gelatin by crosslinking with hitherto uninvestigated isophorone diisocyanate to achieve controlled drug release characteristics. The crosslinked gelatin was insoluble and swellable in biofluids and analyzed by FT-IR and proton NMR, thermal analysis, swellability and biodegradability in simulated biofluids, X-ray diffraction, biocompatibility, and in vitro drug release kinetics and mechanism with 5-Fluorouracil as model drug. Crosslinking decreased the biodegradability and solubility, and enhanced the amorphous character of gelatin. The mild decrease in thermal stability of crosslinked gelatin was attributed to the urea linkage introduced. Drug release predominately occurred via anomalous transport mechanism with mild degradative diffusion. The observed results demonstrated that crosslinked gelatin can be used as a potential carrier to achieve controlled drug release.