Exposure to high altitudes for hours or days is defined as acute hypobaric hypoxia (AHH) condition, which rapidly engages adjustments such as signaling pathways involving inflammation, immune modulation and oxidative stress, whose dysregulation has been described as contributing to the pathophysiology of high-altitude illnesses, due to insufficient acclimatization, such as developing acute mountain sickness (AMS). Given its traditional high-altitude use and bioactive properties, Senecio nutans (S. nutans) extract, or chachacoma (CH), has emerged as a potential therapeutic strategy to mitigate high-altitude related pathobiology. The aim of this study was to evaluate the effects of S. nutans on acclimatization, regarding the status of oxidative stress, inflammation, immune and symptoms associated with AMS in an animal model exposed to AHH. Twenty-eight female Wistar rats (≈3 months old) were randomly allocated into four experimental groups (n = 7 each): normobaric normoxia (NX), normobaric normoxia plus S. nutans administration (NX+CH), acute hypobaric hypoxia (AHH; 48 h exposure), and acute hypobaric hypoxia plus S. nutans administration (AHH+CH). S. nutans was administered subcutaneously at a dose of 80 mg/kg, one hour prior to hypoxic exposure. Outcomes included body weight, food intake, hematological parameters, lung histopathology, pulmonary mRNA expression of HIF-1α, NF-κB, TNF-α, IL-1β, IL-6, and VEGF, and lipid peroxidation in lung tissue assessed by malondialdehyde (MDA) levels. After 48 h of AHH, animals exhibited a decrease in body weight and food intake, increase in hematocrit level and total leukocytes, as well as lung injury characterized by thickening of alveolar walls and inflammatory infiltrates. In addition, AHH induced an increase in pulmonary IL-6 and IL-1β mRNA expression. In contrast, S. nutans administration partially attenuated hypoxia-induced body weight loss, mitigated the rise in hematocrit levels, and reduced lung damage, while returning total leukocyte counts to control levels. Notably, S. nutans also decreased the hypoxia-induced overexpression of IL-6 and IL-1β. Regarding lipid peroxidation, no significant differences were observed among groups. These findings suggest that S. nutans exerts a protective effect against acute hypobaric hypoxia by attenuating inflammatory responses and preserving pulmonary structure, thereby supporting its potential as a preventive strategy to mitigate early pathophysiological alterations associated with high-altitude exposure.