High-altitude locations are fascinating for investigating biological and physiological responses in humans. In this work, we studied the high-altitude response in the plasma and urine of six healthy adult trekkers, who participated in a trek in Nepal that covered 300 km in 19 days along a route in the Kanchenjunga Mountain and up to a maximum altitude of 5140 m. Post-trek results showed an unbalance in redox status, with an upregulation of ROS (+19%), NOx (+28%), neopterin (+50%), and pro-inflammatory prostanoids, such as PGE2 (+120%) and 15-deoxy-delta12,14-PGJ2 (+233%). The isoprostane 15-F2t-IsoP was associated with low levels of TAC (−18%), amino-thiols, omega-3 PUFAs, and anti-inflammatory CYP450 EPA-derived mediators, such as DiHETEs. The deterioration of antioxidant systems paves the way to the overload of redox and inflammative markers, as triggered by the combined physical and hypoxic stressors. Our data underline the link between oxidative stress and inflammation, which is related to the concept of OxInflammation into the altitude hypoxia fashion.