Citrinin (CIT) contamination has been reported in agricultural foods and is known to be nephrotoxic to human and animals. In the present study, the proteomes and transcriptomes of C. podzolicus Y3 treated with or without 10 μg/mL CIT were compared by two-dimensional electrophoresis (2-DE) and RNA sequencing, respectively. The proteomics results showed that there were 23 differentially expressed proteins (DEPs), 8 DEPs were up-regulated and 15 DEPs were significantly down-regulated. Transcriptomic analysis showed that 1208 genes were differentially expressed, 551 (43.05%) DEGs were up regulated and 657 (56.95%) were down-regulated. These results showed that the CIT treatment caused DNA damage, oxidative stress and cell apoptosis in C. podzolicus Y3. CIT treatment also activated the defense response (DNA repair and drug resistance biological process, antioxidative activity and TCA cycle) as well as drug metabolism (synthesize the CIT-degrading enzymes) in yeast cells to respond to CIT stress and degrade CIT.