Cancer is one of the most prevalent chronic diseases of the world. Certain edible mushroom species are rich in antioxidants, which perform a vital role in preventing this risk in manifesting itself. Initial screening was followed by qualitative phytochemical analysis; estimation of total phenolic content, DPPH radical scavenging activity, and the ferric-reducing ability of plasma (FRAP) of the ethanolic and the aqueous extracts of 3 edible medicinal mushroom species, namely, Auricularia polytricha, Macrolepiota procera, and Pleurotus ostreatus. Furthermore, based on promising results from studies of antioxidant activities, these extracts were carried forward to study cytotoxic, antiproliferative, and antiapoptotic effects on breast (MCF-7), colon (COLO-205), and kidney (ACHN) cancer cell lines. Among all the extracts, the aqueous extract of P. ostreatus and the ethanolic extract of M. procera showed the highest cytotoxic effect on all 3 cancer cell lines, especially COLO-205. The scientific data obtained so far show that the aqueous extracts of all 3 species of mushrooms have a remarkable irreversible antiproliferative effect on COLO-205 compared with other cancer cell lines. This decrease in cell viability, morphological changes, and apoptotic hallmarks observed upon treatment with the extracts validated the anticancerous property of these mushroom species.