Macrophages are essential components of the innate immune system and are generally categorized into two functional phenotypes: pro-inflammatory (M1) and anti-inflammatory (M2). The present study investigated the potential immunomodulatory effects of argentatins A and B, triterpenes extracted from Parthenium argentatum (guayule), on M1 macrophage polarization. RAW 264.7 murine macrophages were pretreated with argentatins prior to stimulation with bacterial lipopolysaccharide. Cell viability and nitric oxide (NO) production were determined using MTT and Griess assays, respectively. Phenotype-specific gene and protein expression were quantified via quantitative RT-PCR, luciferase reporter assays, western blotting, and ELISA. The results demonstrated that both argentatins, at non-cytotoxic concentrations, significantly inhibited the production of NO, a hallmark of the M1 phenotype. Specifically, argentatin A attenuated NO production primarily by suppressing the protein expression of inducible nitric oxide synthase (iNOS), while argentatin B exhibited a more pronounced inhibitory effect at the iNOS mRNA level. Mechanistically, this suppression was independent of the NF-κB pathway, as argentatins did not affect IKKβ degradation or NF-κB transcriptional activity. Instead, the anti-inflammatory effect was mediated through the inhibition of p38 and ERK1/2 MAP kinase phosphorylation, resulting in significantly reduced AP-1 activity. These findings indicate that argentatins serve as potent modulators of the innate inflammatory response and represent promising candidates for the treatment of inflammatory pathologies.