Despite advances in lifestyle-based therapy, achieving clinically meaningful reductions in blood lipid levels remains a major challenge in obese men with secondary hypercholesterolemia. Hypoxic exposure encompassing both training sessions and nocturnal rest may offer a novel adjunct to conventional interventions; however, no study has evaluated such a protocol in this population. Twenty sedentary men with obesity-related hypercholesterolemia were randomly allocated to a hypoxic group (H) or normoxic control group (C). Both groups completed an identical two-week high-intensity training program under an individualized calorie-restricted diet, residing at the same lowland location (~100 m above sea level). The H group trained and rested under normobaric hypoxia (FiO2 = 14.4%, simulated altitude ~3000 m, 8 h nightly); C remained under normoxic conditions. The H group demonstrated significantly greater reductions in body mass (-4.1%) and fat mass (-11.0%). Significant reductions in total cholesterol (-20.1%), low-density lipoprotein cholesterol (-21.3%), non-high-density lipoprotein cholesterol (-23.1%), atherogenic index of plasma (-42.4%), and Castelli Risk Index I (-19.4%) occurred exclusively in the H group, accompanied by a strong downward trend in Castelli Risk Index II (p = 0.072). High-density lipoprotein cholesterol did not change; for triglycerides, a clear downward trend was observed in the H group, approaching statistical significance within-group (p = 0.052). The magnitude of cholesterol reduction was significantly associated with body mass and fat loss (r = 0.61-0.67). A two-week intervention combining hypoxic training with nocturnal normobaric hypoxic exposure and caloric restriction produces clinically relevant improvements in lipid profile and body composition in men with obesity-related hypercholesterolemia.