Objectives: Zeaxanthin (ZEN) is known as one of the most important and common xanthophyll carotenoids, possessing multiple therapeutic effects such as strong antioxidant and pro-oxidant behaviour as well as anti-inflammatory effects.   Aim of present study was to investigate protective mechanism of the ZEN in pulmonary arterial hypertension (PAH)  male Wistar rats.     Methods: 60 male albino Wistar rats were randomly divided into sham group, PAH group and ZEN group. Rats in PAH group were subcutaneously injected with 60 mg/kg monocrotaline once to establish the model of PAH.  Meanwhile, rats in PAH + ZEN group were administrated with ZEN (100mg/kg) via oral gavage daily for 4 weeks. After 4 weeks of ZEN administration, we evaluated hemodynamics, harvested the lungs and performed morphometric analysis of the pulmonary vasculature.  Finally, Western blot was conducted to detect the protein expressions of nuclear factor-kappa B (NF-κB), phosphorylated signal transducers and activators of transcription-3 (STAT3),  tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), vascular cell adhesion molecule 1 (VCAM-1) and  intercellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) in lung tissues of rats.    Results: ZEN  treatment attenuated PAH-induced pathological lesions in lung tissues. ​Compared with sham group, mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP) were significantly exacerbated in rats of PAH group (p<0.001). On the contrary, mPAP and RVSP in rats of ZEN  group were both significantly lower than PAH group (p<0.05).  Biochemical results elucidated that ZEN treatment significantly decreased serum levels of TGF-β, TNF-α, IL-1β, and IL-6. In addition, Western blot results demonstrated that protein levels of NF-κB, phosphorylated STAT3, TNF-α, IL-1β, VCAM-1, ICAM-1, and MCP-1 in ZEN group were remarkably lower compared to PAH group.   Conclusions: ZEN administration ameliorates PAH in rats by suppressing macrophage accumulation, reducing oxidative stress and modulating the STAT3/ NF-kB/ TNF-α pathway and promising pharmacological perspectives.