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The aim of the present study was to explore the toxic effects and underlying mechanisms of nickel ions during therapeutic nickel-based alloy-treatment in congenital heart disease by investigating the metal-induced cytotoxicity to the human monocyte-derived macrophage cell line THP-1. THP-1 cells were treated with NiCl2·6H2O (25, 50, 100, 200, 400 and 800 µM) for 24, 48 and 72 h, respectively. MTT was applied to detect THP-1 cell proliferation following NiCl2 treatment. Apoptosis of THP-1 cells was quantified using flow cytometry. Illumina sequencing was used for screening the associated genes, whose mRNA expression levels were further confirmed by quantitative real-time polymerase chain reaction. High concentrations of nickel ions had a significant suppressive effect on cell proliferation at the three concentrations investigated (200, 400 and 800 µM). Treatment with nickel ions (25–400 µM) for 48 h reduced cell viability in a dose-dependent manner. The mRNA expression levels of RELB, FIGF, SPI-1, CXCL16 and CRLF2 were significantly increased following nickel treatment. The results of the present study suggested that nickel ions exert toxic effects on THP-1 cell growth, which may indicate toxicity of the nickel ion during treatment of congenital heart disease. The identification of genes modified by the toxic effects of nickel on THP-1 cells (EPOR, RELB, FIGF, SPI-1, TGF-β1, CXCL16 and CRLF2) may aid in the development of interventional measures for the treatment/prevention of nickel ion-associated toxic effects during the treatment of congenital heart disease.