The severe acute respiratory syndrome produced by COVID-19 is a highly infectious and pathogenic viral infection. Many COVID-19 patients have secondary bacterial infections, which enhance disease and increase death, particularly when requiring invasive mechanical ventilation. One of the most important medicinal mushrooms, Ganoderma lucidum, has been used for food, feed, and medication since the dawn of humanity. The present investigation aims to discover the potential of the medicinal mushroom Ganoderma lucidum inhibited multidrug-resistant isolates from secondary infection of Covid-19 patients. Isolation and identification of urine samples from secondary infection of post-Covid-19 patients and evaluate the antibiotic sensitivity assay, as identification of bioactive compounds, anti-inflammatory and antioxidant activity from Ganoderma lucidum. Totally 6 clinical urine samples were collected from the age group 45 to 60; 3 were male, and 3 were female. In total, nine bacteria and 10 fungi were isolated and identified. As antibiotic sensitivity assays of ceftriaxone, fluoroquinolones, azithromycin and amphotericin, nystatin and fluconazole were performed by the disc diffusion method against bacteria and fungi, the zone of inhibition was maximal in Klebsiella pneumoniae and Fusarium oxysporum. The aqueous and ethanolic extracts of Ganoderma lucidum were analyzed for the bioactive compounds, viz., steroids, flavonoids, alkaloids and phenolic compounds. The effect of the anti-inflammatory activity of the aqueous extract was excellent. The activity of the DPPH assay was maximum in aqueous and ethanolic extracts of all concentrations (100 to 500 ml). Antibiotic resistance could probably rise due to the frequent prescription of broad-spectrum empiric antimicrobials to COVID-19 patients. Hence, Ganoderma lucidum can be exploited to prevent secondary infection in COVID-19 patients.