Introduction: Natural products remain an important source of bioactive compounds for the discovery of new anti-inflammatory agents. Phyla lanceolata has been traditionally used in folk medicine; however, scientific evidence supporting its anti-inflammatory potential is still limited. Therefore, the present study aimed to evaluate the anti-inflammatory activity of organic extracts obtained from the leaves of P. lanceolata. Methods: Leaves of P. lanceolata collected in Cunduacán, Tabasco, Mexico, were sequentially extracted by maceration using solvents of increasing polarity (n-hexane, ethyl acetate, and methanol). The extraction yields were determined gravimetrically. Anti-inflammatory activity was evaluated using the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model. Indomethacin was used as the reference anti-inflammatory drug. Results: Methanol afforded the highest extraction yield (7.93%), followed by ethyl acetate (1.51%) and n-hexane (0.56%). Among the tested extracts, the ethyl acetate extract exhibited the strongest anti-inflammatory activity, producing 55.43% inhibition of ear edema, which was comparable to the inhibition produced by indomethacin (62.67%). The methanolic and n-hexane extracts also reduced inflammation, although with lower inhibitory activity. Conclusions: The results demonstrate that P. lanceolata is a promising source of bioactive compounds with anti-inflammatory properties. In particular, the ethyl acetate extract showed remarkable pharmacological activity, suggesting that compounds of intermediate polarity may contribute to the observed effect. These findings provide a scientific basis for further phytochemical investigations to identify the active metabolites and for additional pharmacological and toxicological studies to evaluate their therapeutic potential and safety.