Cytokine hemoadsorption therapy has been proposed to reduce inflammation in patients with hyperinflammation. However, the clinical benefit of cytokine hemoadsorption therapy during venovenous extracorporeal membrane oxygenation (VV ECMO) is still unclear. The aim of the study was to evaluate the effect and mechanism of small molecular affinity ligand adsorbent (PS-Arg) for cytokine hemoadsorption in a rat model during VV ECMO. Forty-five Sprague–Dawley (SD) rats were divided into three groups: a control group, a VV ECMO group, and an ECMO combined with hemoadsorption group (VV ECMO + HA [ECMO + hemoadsorption] group), with 15 rats in each group. Each experiment was repeated at least three times. The duration of ECMO is 3 hours. After weaning, arterial blood gas analysis, serum cytokine levels, and lung injury of rats were assessed. Then, we performed histological and RNA sequencing analyses of lung tissues. Cytokine hemoadsorption therapy with PS-Arg increased the circulation volume but maintained the stability of blood gases. Polystyrene-arginine significantly reduced the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), lung injury, and macrophage and neutrophil infiltration in the lung. According to the RNA sequencing results, it is associated with the downregulation of inflammation-related signaling pathways. Our findings indicate that cytokine hemoadsorption therapy reduces systemic inflammation and provides lung protection in a rat VV ECMO model by down-regulating components of inflammatory signaling pathways.