--- - |2 Summary The current study aimed to investigate the effects of sildenafil and N‐acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (APT). We developed an APT model using healthy male China big‐ear rabbits (2.7 ± 0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis‐associated molecules, FoxO1, Bad and Bcl‐2, in the lung tissue. Gelatine zymography was used to detect matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N‐acetylcysteine potentiated the haemodynamic‐improving effect of sildenafil and significantly inhibited the oxidative stress response. N‐acetylcysteine combined with sildenafil decreased MMP‐2 and MMP‐9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP‐1 and p‐p38 MAPK. Thus, NAC potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP‐1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT. - 'Clinical and Experimental Pharmacology and Physiology, EarlyView. '