Previous studies showed a potent anti-inflammatory activity of Solanum tuberosum L. polysaccharide (STP), which inhibited pro-inflammatory cytokines and stimulated anti-inflammatory ones in peptic ulcer models. Thus, the main goal of this study was to find out the molecular background of such activity and possible applications in different anti-inflammatory models. This study investigated the anti-inflammatory potential of the polysaccharide STP using model of LPS-induced inflammation in THP-1 macrophage-like cells (on the expression of IL1B, IL6, IL10, TNF, NFKB1, BCL2, NRF2, and BAX—genes involved in the regulation of inflammatory processes and oxidative stress), rat pocket granuloma, and carrageenan-induced oedema models. STP significantly reduced oedema volume, exhibiting a comparable anti-exudative effect to ibuprofen and surpassing the control group. The anti-inflammatory mechanism of STP extends beyond suppression of proinflammatory cytokine (IL1B, IL6, TNF) expression, as it also activates cellular defence mechanisms (NRF2, BCL2, BAX) and expression of anti-inflammatory cytokine (IL10). This complex, multifactorial action suggests that STP may possess significant therapeutic value for inflammatory conditions. The combined functional and molecular findings underscore STP’s potent anti-inflammatory properties, comparable to ibuprofen. © 2025 Elsevier B.V., All rights reserved.