<p>Intestinal mucosal inflammation and epithelial injury can be associated with central inflammatory and behavioral alterations through gut–brain axis-related pathways. This highlights the need for therapeutic strategies that target intestinal inflammatory injury while also attenuating colitis-associated central responses. Here, we evaluated the effects of <i>Paeonia suffruticosa</i> root bark extract (PSE) on dextran sulfate sodium (DSS)-induced colitis and associated neuroinflammatory and behavioral alterations, with a particular focus on intestinal necroptosis-associated signaling. In a DSS-induced colitis model, PSE reduced body weight loss, colon shortening, systemic inflammatory cytokine levels, and tissue injury-associated epithelial cell death, while also attenuating colonic necroptosis-associated signaling. Open-field and tail-suspension tests further showed that PSE improved behavioral indices associated with anxiety- and depression-/despair-like responses in DSS-treated mice. Consistently, PSE reduced inflammatory signaling and glial activation in the hippocampus and prefrontal cortex. In vitro, PSE protected intestinal epithelial cells from injury induced by a necroptosis-triggering combination of a Smac mimetic and zVAD-FMK (SZ), accompanied by reduced ROS production and inhibition of RIP1–RIP3–MLKL pathway activation. Fractionation-guided isolation of PSE identified five major constituents, all of which suppressed SZ-induced cell death and necroptosis-associated signaling at non-cytotoxic concentrations. Network-based analysis further identified putative molecular mediators linking PSE constituents to necroptosis-related pathways. Collectively, these findings suggest that PSE attenuates DSS-induced intestinal inflammatory injury and colitis-associated central inflammatory and behavioral alterations through suppression of necroptosis-associated signaling.</p> Graphical abstract <p></p>