Since the external ear is covered with skin, infections that cause otitis externa are often produced by distinct skin flora in several different areas. Staphylococcus aureus (S. aureus) reproduces the most out of all bacteria isolated from external auditory canal skin culture samples. Proinflammatory cytokines are the main components responsible for tissue damage pathogenesis due to S. aureus. Nimesulide is a nonsteroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 and also demonstrates antioxidant properties. The present study aimed to examine the antibacterial activity of nimesulide against S. aureus and to compare its effectiveness on otitis externa induced by S. aureus in male albino Wistar rats with that of cefazolin. The antimicrobial activity testing was conducted using the Kirby-Bauer disk diffusion method as described by the European Committee on Antimicrobial Susceptibility Testing. To induce otitis externa, we applied 0.5 ml of S. aureus to the ear skin using a hypodermic syringe (S. aureus strain TACK 25923 was dispersed on the 900x10-6 concentration of colony forming units per ml). Nimesulide and cefazolin were administered orally at a dose of 50 mg/kg. The antibacterial activity of cefazolin when used in equal doses (50 µg/ml) was more powerful against S. aureus than nimesulide. However, nimesulide reduced the macroscopic findings (such as oedema and redness) induced by S. aureus better than cefazolin. Additionally, nimesulide inhibited the increase of oxidant and proinflammatory indicators related to S. aureus, while cefazolin was able to inhibit only the increase in proinflammatory indicators. Our results showed that nimesulide was superior to cefazolin in terms of reducing the external ear damage caused by S. aureus. Therefore, nimesulide monotherapy or a combination of nimesulide and cefazolin therapy may be beneficial in the treatment of bacterial otitis externa.