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Obesity is a major global health issue and a primary risk factor for metabolic-related disorders. While physical inactivity is one of the main contributors to obesity, it is a modifiable risk factor with exercise training as an established non-pharmacological treatment to prevent the onset of metabolic-related disorders, including obesity. Exposure to hypoxia via normobaric hypoxia (simulated altitude via reduced inspired oxygen fraction), termed hypoxic conditioning, in combination with exercise has been increasingly shown in the last decade to enhance blood glucose regulation and decrease the body mass index, providing a feasible strategy to treat obesity. However, there is no current consensus in the literature regarding the optimal combination of exercise variables such as the mode, duration, and intensity of exercise, as well as the level of hypoxia to maximize fat loss and overall body compositional changes with hypoxic conditioning. In this narrative review, we discuss the effects of such diverse exercise and hypoxic variables on the systematic and myocellular mechanisms, along with physiological responses, implicated in the development of obesity. These include markers of appetite regulation and inflammation, body conformational changes, and blood glucose regulation. As such, we consolidate findings from human studies to provide greater clarity for implementing hypoxic conditioning with exercise as a safe, practical, and effective treatment strategy for obesity.