As potential substitutes for polybrominated diphenyl ethers (PBDEs), organophosphate flame retardants (OPFRs) have been frequently detected in the environment. However, the genotoxicity induced by these OPFRs has rarely been described, and the results reported in previous studies are conflicting and inconsistent. The present study aimed to determine how OPFRs induced genetic toxicity in vivo. Using Chinese rare minnow as a model, the toxicity of three OPFRs was screened with RNA-seq. To verify the OPFR-induced genotoxicity, alkaline comet assay, cell apoptosis analysis, HPLC-based DNA methylation assay, 8-OHdG assay, bioconcentration and biotransformation investigation were performed. According to transcriptomic data, TDCIPP exposure substantially altered the pathways related to DNA damage, including the cell cycle, DNA replication, Fanconi anemia pathway, p53 signaling pathway, and various DNA repair pathways. Although TBOEP and TPHP did not affect DNA damage, TDCIPP induced DNA damage in a dose-dependent manner. TDCIPP also induced apoptosis, altered the activities of caspase-3 and -9, and increased the 8-OHdG levels, while a significant difference in the levels of DNA methylation induced by OPFRs was not observed. Based on these results, TDCIPP induced DNA oxidative damage, eventually leading to genotoxicity in vivo.