The effect of low-frequency ultrasound (US, 20 kHz, 104 W) on the degradation of anticancer drug irinotecan (IRI) using reactive electrochemical membrane (REM) was investigated. Results demonstrated that higher k value (0.103 min−1) and mineralization efficiency (94.6%) as well as lower energy consumption (0.906 Wh L−1) were observed in US-REM system. The effects of influence factors including US power, volume flow rate, current density and initial IRI concentration on the degradation of IRI were studied in US-REM system. The relative contributions of •OH, SO4•− and O2•− (indirect oxidation) to IRI degradation using REM were all increased with the assistance of US. The production rate of •OH using US-REM increased by 19.7% compared with that using REM. Seven intermediates of IRI degradation using both REM and US-REM were identified, and the main degradation pathways of IRI were hydroxylation, oxidation and ring cleavage. The enhanced degradation and mineralization of IRI in US-REM system could mainly be attributed to higher •OH production and higher contribution of free radicals.