The modification of approved drugs is an established medicinal-chemistry approach that can reduce some of the uncertainty associated with completely new chemical entities while providing opportunities to improve activity or introduce additional biological effects. Nabumetone is a non-acidic non-steroidal anti-inflammatory prodrug used mainly for painful inflammatory disorders such as osteoarthritis and rheumatoid arthritis. During the last decade, its chemically accessible framework has been employed in the synthesis of structurally diverse derivatives containing pyrazoline, isoxazoline, pyrimidine, thiazolidinone, sulfonamide, triazole, pyridine, and other five-membered heterocyclic systems. The reported compounds exhibited anti-inflammatory, antibacterial, antifungal, antiproliferative, and anticancer activities. This review summarizes their synthetic relationships, structural diversity, biological importance, and the principal considerations that should guide further investigation of nabumetone-derived compounds.