The bioremediation of heavy metals contaminated soils with macrofungi is a new and promising approach; hence Agaricus bisporus (Large) sing has potentially shown accumulating ability to Cd contamination. This study focused on the tolerance response by A. bisporus to different contents of Cd in the closed cup and the flat stage of fruiting body development. The contents of Cd, soluble protein, sugar, low molecular weight organic acids (LMWOAs), and antioxidant activity were investigated. The bioaccumulation factor and transfer factor results revealed that Cd accumulated in the cap of A. bisporus more than that in the stipe with the highest content being 18.38 mg kg−1 dry weight at the closed cup stage under 414.28 mg kg−1 Cd stress. High Cd content stress increased soluble protein, proline, and malonaldehyde contents at both stages; while higher peroxidase, catalase, ascorbic acid peroxidase activities, and LMWOAs contents were only recorded at the closed cup stage. On the other hand, Superoxide dismutase activities and soluble sugar content showed a complex trend. Overall, these results have successfully established that A. bisporus could resort to modulating its metabolism to avoid the destructive effects of Cd stress and could successfully accumulate Cd in the soil, which is a promising prospect for the remediation of Cd-contaminated soils.