This study aimed to investigate the effect of eccentric exercise on exercise‐induced muscle damage (EIMD) and inflammation on high‐altitude‐induced venous gas emboli (VGE). Subjects were exposed to an altitude of 24,000 ft. for 90 min, with either prior eccentric exercise (ECC) or no exercise (Control) 24 h before. Blood samples were collected at baseline (T0), before (T1), and after (T2) altitude exposures. VGE load was evaluated using the Eftedal‐Brubakk (ΕΒ) scale. Creatine kinase (CK) and myoglobin were used to assess muscle damage, while interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF‐α), C‐reactive protein (CRP), and fibrinogen were used to evaluate inflammation. ECC showed higher EB‐scores during altitude exposures [median(range), 3(0–5)] than Control [1(0–4), p = 0.019]. Increases in myoglobin (+35%, p = 0.012), CK (+130%, p < 0.001), IL‐6 (+72%, p = 0.02), and CRP (+63%, p = 0.004) were observed from T0 to T1 in ECC, but not Control. Significantly higher levels of myoglobin (p = 0.033), CK (p < 0.001), IL‐6 (p = 0.016), and CRP (p = 0.002) were noted in the ECC compared to Control at T1. IL‐6 increased from T1 to T2 in ECC (p = 0.005), with higher levels than Control at T2 (p = 0.046). A correlation was found between EB‐scores and T1 myoglobin levels (rs = 0.450; p = 0.004), and to T1‐T2 IL‐6 changes (rs = 0.396; p = 0.037). Eccentric EIMD followed by inflammation is associated with a higher decompression strain, with VGE load aggravating systemic inflammation.