We present a bioenergetics-based approach to analyze the chronic effects and growth toxicity mode of action in tilapia Oreochromis mossambicus exposed to waterborne As and to predict fish growth under different exposure scenarios. 7-day exposure bioassays showed that tilapia accumulate As when exposed to waterborne As. We conducted growth bioassays to assess chronic As toxicity to tilapia. We incorporated a universal ontogenetic growth model with the DEBtox theory to explore the mode of action of As toxicity. Our results show that the specific growth rates of exposed tilapia are inversely proportional to As concentrations and are calculated as 0.76% d−1 in 0 μg mL−1, 0.57% d−1 in 1 μg mL−1, 0.2 % d−1 in 2 μg mL−1, and 0.04% d–1 in 4 μg mL−1 As, respectively. We showed that the internal threshold concentration did not change significantly with time, demonstrating that the critical body residue approach is applicable for As toxicity assessment. We distinguished between three modes of action of As, including direct effects on growth and indirect effects by way of maintenance and food consumption. Our results support that decreased feeding accounts for the growth decrease in the case of feeding ad libitum. The feeding decrease model also illustrates the growth trajectories of tilapia during the entire whole life span, suggesting that the maximum biomass of tilapia are 1038.75 g in uncontaminated water and 872.97 g in 1 μg mL−1, 403.06 g in 2 μg mL−1, and 336.65 g in 4 μg mL−1 As, respectively. We suggest that considering modes of action in ecotoxicology not only improves our understanding of the toxicities of chemicals, it is also useful in setting up models and avoiding pitfalls in species- and site-specific environmental risk assessment. This proposed framework for tilapia gives preliminary information relevant to aquacultural and ecologic management.