Macrofungi are well-known as edible-medicinal mushrooms, which belong mostly to Basidiomycota, with a few from Ascomycota. In recent years, macrofungi have been recognized as a rich resource of structurally unique secondary metabolites, demonstrating a wide range of bioactivities, including anti-tumor, antioxidant, anti-inflammatory, antimicrobial, antimalarial, neuro-protective, hypoglycemic, and hypolipidemic activities. This review highlights over 270 natural products produced by 17 families of macrofungi covering 2017 to 2023, including their structures, bioactivities, and related molecular mechanisms.