The widespread presence of microplastics (MPs) has garnered attention owing to their possible adverse effects. However, the cardiotoxicity of MPs and their underlying mechanism remains unclear. N6-methyladenosine (m6A) modification contributes to post-transcriptional modulation of gene expression, but whether this modification is relevant to MP-induced cardiotoxicity is unknown. First, we detected damage to the myocardial tissue among MP-exposed and -unexposed (control) mice by staining them with hematoxylin and eosin, Masson trichrome, and Oil Red O. Then, we comprehensively measured the transcriptome-wide m6A methylome and m6A-altered genes using high-throughput sequencing assays, such as methylated RNA immunoprecipitation sequencing and RNA sequencing. Our data indicated MP-induced myocardial inflammatory injury and histological alterations in vivo, evidenced by the severity of cardiac fibrosis and increased lipid accumulation. We found 878 increased and 316 decreased methylation peaks mostly distributed in the 3' UTR among the MP-exposed group compared with the control group. We found 779 upregulated and 340 downregulated genes in the MP-exposed group. In addition, conjoint analysis of results from the two high-throughput sequencings showed that 109 and 11 hypermethylated genes were upregulated and downregulated, respectively; 12 and 21 hypomethylated genes were upregulated and downregulated, respectively. Results of the cross-link analysis showed that several potential signals, such as ECM-receptor interactions, cell adhesion molecules, cytokine-cytokine receptor interactions, and NF-κB signaling, contributed to MP-induced cardiotoxicity. Our findings indicated that m6A modifications of genes were involved in MP-induced cardiotoxicity and reported new information regarding the chronic cardiotoxicity caused by MP exposure in mice.Copyright © 2023 Elsevier Ltd. All rights reserved.