Imbalanced oxygen availability is detrimental to normal cell function. Oxygen-sensitive cells such as cardiomyoblasts experience severe irreversible pathophysiological damage under conditions of reduced oxygen availability, such as hypoxia. A number of natural therapeutic agents have been explored for their potential cytoprotective effects, of which medicinal mushrooms are an important source. Ganoderma lucidum, commonly known as lingzhi, is one such mushroom that has been elaborately studied for its potential pharmacological properties. In this study, aqueous and alcoholic extracts of a natural Himalayan variety of G. lucidum were evaluated for their efficiency as remedial agents in treating hypoxic injury to H9c2 cardiomyoblasts. The alcoholic extract of G. lucidum effectively restored cellular viability at a concentration of 600 μg/mL and aided in maintaining cellular redox balance under hypoxia. Substantial reduction in caspase-3 and -7 activation was observed with fluorescent-activated cell sorting. Alcoholic extract of G. lucidum minimized oxidative stress as indicated by measuring reactive oxygen species, lipid peroxidation, and reduced glutathione-to-oxidized glutathione ratio, and also by determining changes in hypoxia-inducible factor 1α and associated genes. To ascertain these positive outcomes of administration of G. lucidum extracts, certain phytoconstituents (nucleobases and flavonoids) were identified using high-performance thin-layer chromatography; antioxidant potential was also evaluated. Results indicated that both extracts contained notable quantities of nucleobases and flavonoids. The extracts also effected high free radical scavenging activities.