A technique combining ultrasonic-assisted Fenton oxidation for the degradation of tri(2-chloroethyl) phosphate (TCEP) was developed. The Box-Behnken response surface method was used to optimize the reaction parameters. The degradation pathways and ecological toxicity changes of TCEP were investigated using density functional theory (DFT) calculations, liquid chromatography-mass spectrometry (LC-MS) analysis, and toxicity software (T.E.S.T.). The results indicated that under optimal conditions (initial pH = 3, ultrasonic power of 360W, and oxidant dosage of 400mg/L), the ultrasonic-Fenton system was capable of effectively degrading TCEP, achieving a degradation rate of 85.8%. Reactive species in the system, such as hydroxyl radicals, preferentially attacked the reaction sites in the TCEP molecules with lower Laplace bond order (LBO) values (weaker chemical bonds), higher negative surface electrostatic potential (ESP) values (higher electron density), and lower reaction energy barriers (easier reaction occurrence), such as the P-O bond cleavage energy barrier of 126.56kJ/mol and the dechlorination reaction energy barrier of 150.79kJ/mol. LC-MS analysis confirmed that the primary degradation pathways of TCEP involved P-O bond cleavage and dechlorination. Toxicity assessment showed that TCEP itself exhibited high bioaccumulation potential and mutagenicity. Hydroxylated intermediates generated during the initial degradation phase exhibited significantly increased toxicity, with the oral LD₅₀ in rats reaching the "toxic" level defined by T.E.S.T. (LD₅₀<50mg/kg), and potential developmental toxicity. However, toxicity was significantly reduced after complete mineralization. The predictive modeling approach provided convenient and effective theoretical support for the degradation pathways and ecological toxicity evaluation of TCEP.