To compare the toxicities of a chlorinated and a nonchlorinated organophosphorus flame retardant (OPFR) in this study, adult calms (Corbicula fluminea) were exposed to tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tributyl phosphate (TNBP) at 20, 200, and 2000 μg/L for 30 days. Toxicity screening using transcriptomics indicated that the apoptosis pathway was significantly affected in the groups exposed to 2000 μg/L TDCIPP and TNBP (p ≤ 0.05), and this finding was further confirmed by the protein interaction network. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay suggested that TDCIPP and TNBP can cause apoptosis. The significant (p ≤ 0.05) increases in the activities of caspases 3 and 8 obtained with all treatments and in that of caspase 9 obtained with 2000 μg/L exposure treatments indicated the presence of mitochondria-dependent and mitochondria-independent apoptosis. Interestingly, a noticeable dose-dependent increase in DNA damage was observed in all treatments, resulting in apoptosis. Therefore, our results demonstrate that TDCIPP and TNBP induce DNA damage and apoptosis in C. fluminea, which indicates that these chemicals pose an ecological risk to benthic organisms. Moreover, through a similar mechanism of action in apoptosis, TDCIPP induced more serious toxicity than TNBP, which indicated that chlorination or differences in structure-specific metabolism could be key factors influencing toxicity.