Chlorine dioxide (ClO2) has been promoted as an alternative disinfectant because of its high disinfection efficiency and less formation of organic disinfection by-products (DBPs). However, particle-associated microorganisms could be protected during the disinfection process, which decreases the disinfection efficiency or increases the required dosage. Besides, the formation of inorganic disinfection by-products is a significant concern in environment health. Ultrasound (US)-combined disinfection methods are becoming increasingly attractive because they are efficient and environmentally friendly. In this study, US was introduced as an enhancement method to identify its influence on ClO2 demand reduction and to minimize the production of potential DBPs for secondary effluents disinfection. Fecal coliform was used as an indicator, and DBPs, including trichloromethane (TCM), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), chlorite (ClO2−), and chlorate (ClO3−), were analyzed to observe the potential DBPs formation. Results show that US pretreatment could reduce half of ClO2 dosage compared with ClO2 disinfection alone for the same disinfection efficiency, and that an input power density of 2.64kJ/L pretreatment with the 1.5mg/L ClO2 was enough to meet the discharge requirement in China (i.e., fecal coliform below 1000CFU/L for Class 1A) for secondary effluent disinfection, and the ClO2− concentration in the disinfection effluent was only 1.37mg/L at the same time. Furthermore, the different effects of US on the two processes (US as pretreatment and simultaneous US/ClO2 disinfection) were also analyzed, including deagglomerating, cell damage, and synergistic disinfection as well as degasing/sonolysis. It was proved that the production of TCM, DCAA, and TCAA was insignificantly influenced with the introduction of US, but US pretreatment did reduce the production of ClO2− and ClO3− effectually. In general, US pretreatment could be a better option for disinfection enhancement methods combined with ClO2 in terms of both disinfection efficiency and disinfection by-product formation.