Zinc homeostasis is regulated by the SLC39A/ZIP, SLC30A/ZnT, and metallothionein (MT) protein families. The association of zinc homeostasis with acute myeloid leukemia (AML) is unclear. We previously demonstrated that zinc depletion by TPEN triggers apoptosis in NB4 AML cells with the degradation of PML-RARα oncoprotein, suggesting that zinc homeostasis may be associated with AML. The primary aim of this study was to explore the expression pattern and prognostic roles of zinc homeostasis-related genes in AML. Bioinformatics analyses were performed using integrated datasets from the TCGA and GTEx projects. The GEPIA tool was used to analyze the differential expression of zinc homeostasis-related genes. Correlations between zinc homeostasis-related genes were assessed with Spearman's correlation coefficient. OncoLnc was used to evaluate the prognostic roles of zinc homeostasis-related genes with Kaplan-Meier and Cox regression models. In both NB4 and U937 cells, the transcriptional regulation of zinc homeostasis-related genes by zinc depletion was detected through qPCR. We found that multiple ZIPs, ZnTs, and MTs were differentially expressed and correlated in AML tumors. In AML patients, higher expression of ZIP4 and lower expression of ZnT5 and ZnT7 predicted poorer survival. We further found that zinc depletion by TPEN upregulated ZIP7, ZIP9, ZIP10, ZIP13, and ZnT7 and downregulated ZIP14, ZnT1, ZnT6, and most of the positively expressed MTs in both NB4 and U937 AML cells. Our findings suggest high expression of ZIP4 and low expression of ZnT5 and ZnT7 as potential risk factors for the prognosis of AML. Zinc homeostasis may be a potential therapeutic target for AML, deserving further exploration.