Cryptocaryon irritans cause massive losses in the mariculture industry and are among the most threatening pathogens affecting teleost species. Copper‑zinc alloy (CZA) surface contact effectively kills C. irritans within minutes. Thus, this study employed integrated metabolomics and proteomics analysis to investigate the killing mechanism of CZA against C. irritans. Moreover, malondialdehyde contents, CuZn-SOD, and ATPase activities were evaluated. Proteomics analysis identified 142 differentially expressed proteins (DEPs), including 91 (59 upregulated, 32 downregulated), 92 (42 upregulated, 50 downregulated), and 43 (17 upregulated, 26 downregulated) DEPs at 0.5 h, 1 h, and 0.5 h vs 1 h of contact treatment with the CZA surface, respectively. Similarly, the metabolomic analysis identified 377 differentially expressed metabolites (DEMs). There were 237 (94 upregulated, 143 downregulated), 264 (112 upregulated, 152 downregulated), and 193 (101 upregulated, 92 downregulated) DEMs at 0.5 h, 1 h, and 0.5 h vs 1 h of contact treatment with the CZA surface, respectively. KEGG-based integrative analyses revealed that CZA exposure significantly enriched proteins and metabolites involved in oxidative phosphorylation, purine, pyrimidine, cysteine, and methionine metabolism. Notably, CZA exposure inhibited the TCA cycle, disrupting energy metabolism, as evidenced by downregulation of key TCA proteins, including citrate synthase and malate dehydrogenase, and metabolites like succinic and malic acids at both 0.5 h and 1 h of CZA treatment. Prolonged CZA exposure also affected protein metabolism, with significant downregulation of ribosomal protein S3a (RPS3a) and proteasome activity. Additionally, CZA surface contact downregulated key proteins involved in pyrimidine (DHFR-TS), purine (RRM1), and cysteine and methionine metabolism (AHCY), leading to disturbances in the methionine cycle, suppression of glutathione metabolism, and alterations in cellular redox status. Quantitative polymerase chain reaction (qPCR) analysis confirmed the upregulation of citrate synthase, proteasome subunit alpha type, and adenosylhomocysteinase with prolonged CZA exposure. Additionally, extended CZA exposure significantly decreased the MDA content due to the increased CuZn-SOD activity. Moreover, CZA exposure reduced Ca2+/Mg2+-ATPase and Na+/K+-ATPase activities. Altogether, CZA surface contact caused metabolic disruption, lipid peroxidation, and osmotic imbalance of C. irritans tomonts, highlighting the broad molecular impact of CZA on cellular processes. [Display omitted] • Metal copper, zinc, and alloy (CZA) effectively kill C. irritans. • Integrated metabolomics and proteomics analysis evaluated the CZA-killing mechanism against C. irritans. • CZA treatment inhibited the TCA cycle, disrupting energy metabolism. • CZA surface contact caused metabolic disruption, lipid peroxidation, and osmotic imbalance in C. irritans tomonts. [ABSTRACT FROM AUTHOR]