Honey and propolis are the honey bee-derived products with a long history of consumption by humans for health purposes. Both of these substances consist of a wide spectrum of vital compounds especially phenolics and flavonoids that are capable of exerting beneficial clinical effects on health. The antimicrobial, anti-metastatic, anticancer, anti-inflammatory, antioxidant, and anti-proliferative activities of honey ingredients and antiviral, antifungal, antimicrobial, anesthetic, anti-inflammatory, antioxidant, anti-protozoal, anticancer, antihepatotoxic, antihypertensive, and cytotoxic properties of propolis make these substances potential candidates for therapeutics. Honey has been found effective in the treatment of diabetes mellitus, cardiovascular disorders, respiratory ailments, neurological abnormalities, gastrointestinal defects, skin ulcerations, ophthalmic defects, wounds, peptic ulcers, and different types of carcinomas. Likewise, propolis also exhibits potential role in the management of chronic kidney disease, neurological disorders, tumors, ulcers, chronic periodontitis, atherosclerosis, gastrointestinal defects, and wounds. Evidences suggest honey and propolis as potential phyto-derived clinico-pharmacological agents for effective treatment of different diseases.