Chlorination is widely used to disinfect drinking water to keep humans safe from microorganisms. During chlorination, chlorine and its compounds react with contaminants to form disinfection by-products (DBPs). Toxicological and epidemiological studies have demonstrated that trihalomethanes (THMs) are the most widely investigated DBPs in drinking water, and their exposure has been associated with some adverse health effects. However, studies about risk characteristics in this field are limited. We estimated the health risks of THMs exposure in drinking water through multi-pathways, and systematically analyzed the factors influencing health risks of THMs in Wuxi, China. A total of 488 drinking water samples were collected and analyzed for THMs from four water treatment utilities from 2008 to 2016 in Wuxi. And water exposure parameters were obtained from 602 participants by structured questionnaires. The median concentration of THMs ranged from 6.71 μg/L to 9.18 μg/L. The cumulative cancer risk of THMs exposure through multi-pathways was 1.26 × 10−4, and CHBr2Cl made the largest contribution to the total cancer risk (48.25%). The non-cancer risk of THMs exposure was 2.02 × 10−1. Health risks of the exposure to THMs in drinking water in summer were significantly higher than that in winter (P = 0.0003 for cancer risk, and P = 5.95 × 10−7 for non-cancer risk). In our study, the average individual disability-adjusted life years (DALYs) lost was 1.27 × 10−4 per person-year (ppy). This study attempted to use DALYs for risk assessment of THMs, which will provide useful information for risk comparison and prioritization of hazards in drinking water. This suggested that potential higher risk might exist, and possible measures could be considered to decrease the health risks.