Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually used to alleviate pain and Inflammation. The widespread use of NSAIDs has caused the risk and side effects of these drugs commonly increase. Objectives: This study aimed to examine the anti-inflammatory and antinociceptive activities of ethanolic extract of propolis (EEP) in male mice and rats. Methods: In this experimental study, EEP was prepared and administered in doses of 100, 200, and 400 mg/kg of body weight. The anti-inflammatory potential was assessed by inflammatory models of xylene-induced ear edema and cotton pellet granuloma tests, whereas the antinociceptive potential was assessed by formalin and acetic acid-induced writhing methods. Results: The EEP at doses of 100 (P < 0.05), 200 (P < 0.001) and 400 mg/kg (P < 0.001) significantly diminished the foundation of edema caused by xylene. A significant decrease was seen in granuloma weight in EEP at doses of 200 (P < 0.001) and 400 mg/kg (P < 0.001). The extract caused a significant decrease in licking time at first phase in EEP at 100 (P < 0.01), 200 (P < 0.001), and 400 mg/kg (P < 0.001). A significant decrease was observed (P < 0.001) in licking time at the second phase in EEP at doses of 100, 200, and 400 mg/kg. In the writhing model, a significant decrease was observed in the number of writhes in EEP at doses of 100 (P < 0.05), 200 (P < 0.001), and 400 mg/kg (P < 0.001). Conclusions: The findings of this research showed that the ethanolic extract of propolis has considerable anti-inflammatory and antinociceptive activities.