Continuous monoculture can increase plant morbidity and reduce crop yields. However, the Ganoderma lucidum mushroom possesses unique nutrient acquisition methods and displays an altered response to the generation of reactive oxygen species (ROS). The effects of continuous cropping on G. lucidum remain unclear. Here, we investigated the effects of consecutive monoculture soil on the yield, bioactive components, antioxidant properties, nutrient metabolism, and enzyme activity of G. lucidum. The results showed no significant differences in terms of yield between the control check and treatment groups after 2 years. However, the content of polysaccharides and triterpenoids after 2 years of treatment and the content of total phenols and flavonoids after 3 years of treatment significantly increased. Moreover, the antioxidant activity (AOA) of the polysaccharides under consecutive monoculture soil treatments also significantly increased. These differences were caused by changes in nutrient metabolism and the activities of antioxidant and ligninolytic enzymes. Under continuous monoculture soil treatment, the content of reducing sugars, water-soluble sugars, free amino acids, and water-soluble proteins significantly increased. The activities of superoxide dismutase, manganese peroxidase, and lignin peroxidase increased with the time of continuous monoculture, while the activities of peroxidase, catalase, and laccase decreased. The increase in ligninolytic enzymes was postulated to mediate the ROS scavenging ability of G. lucidum. In conclusion, continuous cropping soil could increase the levels of bioactive components and AOAs of G. lucidum.