Global food production faces many challenges, including climate change, a water crisis, land degradation, and desertification. These challenges require research into non-traditional sources of human foods. Edible mushrooms are considered an important next-generation healthy food source. Edible mushrooms are rich in proteins, dietary fiber, vitamins, minerals, and other bioactive components (alkaloids, lactones, polysaccharides, polyphenolic compounds, sesquiterpenes, sterols, and terpenoids). Several bioactive ingredients can be extracted from edible mushrooms and incorporated into health-promoting supplements. It has been suggested that several human diseases can be treated with extracts from edible mushrooms, as these extracts have biological effects including anticancer, antidiabetic, antiviral, antioxidant, hepatoprotective, immune-potentiating, and hypo-cholesterolemic influences. The current study focuses on sustainable approaches for handling edible mushrooms and their secondary metabolites, including biofortification. Comparisons between edible and poisonous mushrooms, as well as the common species of edible mushrooms and their different bioactive ingredients, are crucial. Nutritional values and the health benefits of edible mushrooms, as well as different biomedical applications, have been also emphasized. Further research is needed to explore the economic sustainability of different medicinal mushroom bioactive compound extracts and their potential applications against emerging diseases such as COVID-19. New approaches such as nano-biofortification are also needed to supply edible mushrooms with essential nutrients and/or to increase their bioactive ingredients.