The aim of this systematic review was to investigate new research on the antioxidant, anti-acetylcholine, antimicrobial, and antitumor activity of genus Schizophyllum, as well as to describe the mycochemical profiles. A summary was made on the published studies in the five-year period from 2017 to 2022, with the focus on the most investigated species of this genus, S. commune. Data were obtained through various scientific online databases, including Google Scholar, Semantic Scholar, PubMed, Science Direct, Elsevier, and Wiley Online Library using specific keywords. Out of 918 records published between 2017 and 2022, a total of 44 peer-reviewed studies were included in qualitative synthesis. Most examined compounds were glucans isolated from the submerged cultivation of S. commune, even though many studies reported proteins, phenolics, and some other secondary metabolites such as flavonoids, saponins, steroids, tannins, triterpenoids, etc. Schizophyllan (SPG), one of the most studied β-glucans isolated from S. commune, has been utilized in clinical trials to treat patients receiving anticancer therapy as an immunopotentiator. Considering the enormous biopotential of genus Schizophyllum, specifically S. commune and S. radiatum, additional attention should be paid to identify the biomolecules more accurately and focus on their antitumor and anti-acetylcholinesterase properties, since they proved to have great prospects in the pharmaceutical and nutraceutical industries.