White Hypsizygus marmoreus is a popular edible mushroom. Its mycelium is easy to be contaminated by Penicillium, which leads to a decrease in its quality and yield. Penicillium could compete for limited space and nutrients through rapid growth and produce a variety of harmful gases, such as benzene, aldehydes, phenols, etc., to inhibit the growth of H. marmoreus mycelium. A series of changes occurred in H. marmoreus proteome after contamination when detected by the label-free tandem mass spectrometry (MS/MS) technique. Some proteins with up-regulated expression worked together to participate in some processes, such as the non-toxic transformation of harmful gases, glutathione metabolism, histone modification, nucleotide excision repair, clearing misfolded proteins, and synthesizing glutamine, which were mainly used in response to biological stress. The proteins with down-regulated expression are mainly related to the processes of ribosome function, protein processing, spliceosome, carbon metabolism, glycolysis, and gluconeogenesis. The reduction in the function of these proteins affected the production of the cell components, which might be an adjustment to adapt to growth retardation. This study further enhanced the understanding of the biological stress response and the growth restriction adaptation mechanisms in edible fungi. It also provided a theoretical basis for protein function exploration and edible mushroom food safety research.