Argemone mexicana L. is a widely used plant in Mexican traditional medicine to treat inflammatory and nervous medical conditions. It has been subjected to several pharmacological and chemical studies in which acute anti‐inflammatory activity is indicated. This work aimed at finding an extract and fraction with anti‐inflammatory activity by means of 2‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced auricular edema. Afterward, the extract and the fraction were tested on neuroinflammation caused by lipopolysaccharides (LPS). Treatments obtained from A. mexicana included the methanolic extract (AmMeOH), a fraction extracted with ethyl acetate (AmAcOEt), and four sub‐fractions (AmF‐1 to AmF‐4), which were evaluated in auricular edema with the TPA assay. Both treatments with the most significant inhibitory effect were employed to test these in the LPS neuroinflammation model. AmAcOEt and AmF‐3 induced a higher inhibition of edema (%), and both diminished ear inflammation when viewed under a microscope. These treatments also raised an increase in spleen, but not in brain of mice with neuroinflammation. They were able to decrease the concentration of proinflammatory cytokines (TNF‐α, IL‐1β, and IL‐6) in both organs. Furthermore, the accumulation of amyloid‐β (Aβ) in hippocampus was not visible. AmF‐3 contains the flavonoids isoquercetin, luteolin, and rutin, the former being the most concentrated.