Caffeic acid phenethyl ester (CAPE) is an important active component of propolis, which is derived from honeybee hives. It has received increasing attention in a variety of medical and pharmaceutical research, due to its anti-oxidant, antiproliferative, anti-inflammatory, antiviral and antifungal activity, in addition to its antineoplastic properties. Besides the use of CAPE as an antioxidant and anti-inflammatory agent in a number of in vivo studies of ear disease, its beneficial effects have been reported in the treatment of cancer, arthritis, allergies, heart disease, diabetes, kidney disease, liver disease and neurological disease. CAPE influences a number of biochemical pathways, as well as several targets involved in ear diseases, in particular, in ototoxicity. The protective effects of CAPE in ototoxicity, which may be induced by a number factors, including lipopolysaccharides, hydrogen peroxide and streptomycin, are evaluated and discussed in the present review.