Mushrooms are excellent sources of nutraceuticals and have attracted much interest as functional foods. In this work the inhibitory capacity of six macrofungus (Coprinus comatus, Macrolepiota mastoidea, Agaricus campestris, Lycoperdon utriforme, Macrolepiota procera, and Leucoagaricus leucothites) against key enzymes related to diabetes type II (α-amylase, α-glucosidase), Alzheimer's disease [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] was assessed for the first time. The antioxidant properties (total antioxidant capacity, metal chelating, ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging assays) and phenolic contents of the selected mushroom species were also evaluated. We found that L. utriforme had the highest enzyme inhibitory activity (0.97 mg galantamine equivalents (GALAE)/g extract, 1.33 mg GALAE/g extract, 0.22 mmol acarbose equivalents (ACAE)/g extract, and 2.97 mmol ACAE/g extract against AChE, BChE, α-amylase, and α-glucosidase, respectively). A widely consumed mushroom species namely A. campestris possessed the highest phenolic content (15.63 mg GAE/g extract) and the maximum antioxidant potential against DPPH, ABTS, FRAP, and CUPRAC. Experimental data collected in the present study support the use of these mushrooms specially L. utriforme and A. campestris as functional foods for the management and/or prevention of diabetes type II, Alzheimer's disease, and oxidative stress related complications.