The control of the most important pest of stored maize, the weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), is mainly achieved with the use of pyrethroid insecticides. However, the intensive use of these compounds has led to the selection of resistant populations and has compromised the control efficacy of this insect pest. Here, the toxicity of indoxacarb for a potential use in the control of S. zeamais was assessed on 13 Brazilian populations. Concentration—mortality bioassays, in the presence of synergists (piperonyl butoxide, triphenyl phosphate, and diethyl maleate), were used to assess potential metabolic-based indoxacarb resistance mechanisms. We also assessed the behavioral (locomotory) responses of these populations to indoxacarb exposure. The results showed significant differences between the populations (LD50 values ranged from 0.06 to 13.99 mg a.i/kg of grains), resulting in resistance ratios of >200-fold between the least (Canarana-MT) and the most (Espirito Santo do Pinhal-SP) susceptible populations. The results obtained with synergized indoxacarb suggest the involvement of esterases and glutathione-S-transferases on indoxacarb action, and also suggest the involvement of cytochrome P450-dependent monooxygenases as a potential indoxacarb resistance mechanism in Brazilian populations of S. zeamais. Although indoxacarb-induced behavioral avoidance varied among populations, some resistant populations (e.g., Canarana-MT) were able to reduce exposure to indoxacarb by spending more time in the nontreated areas. Collectively, our findings indicate that the behavioral (locomotory) and physiological responses of these insects may compromise the control efficacy of oxadiazine insecticides (e.g., indoxacarb) in Brazilian populations of S. zeamais.