Although pyrethroids are increasingly being used to control a number of agricultural insect pests, especially the cotton leafworm, Spodoptera littoralis (Boisd.), pyrethroid resistance is a major obstacle limiting effective control. With the aim of maintaining the effectiveness of pyrethroids in managing pests, a study was undertaken to evaluated the effectiveness of oxidase and esterase inhibitors for synergizing pyrethroids in S. littoralis larvae. Compared with the insecticide-susceptible strain (L-SS) of S. littoralis, the resistance ratio (RR) in the field population (F-RS) was 271.43–fold to cypermethrin. The use of profenofos as an esterase inhibitor significantly increased larval susceptibility to cypermethrin in the F-RS strain, with a synergy ratio (SR) of up to 192.57–fold. Significant inhibition of esterase by profenofos in the F-RS strain was found in vivo. Also, piperonyl butoxide (PB) as an oxidase inhibitor had slight effect of cypermethrin toxicity, so its addition is not a solution for pyrethroid resistance. Thus, modifying the toxicity of cypermethrin by mixing it with organophosphorus compounds (OPs) increased its toxicity and decreased the population of S. littoralis, which is a successful strategy for managing pyrethroid resistance.