In this study, we investigated the toxic effects of benzene to the nematode Caenorhabditis elegans in an integrative manner, using computational behavior and toxicogenomics analyses, along with survival and reproduction. Benzene exposure led to changes in locomotive behavior and reproduction decline in C. elegans. Microarray followed by pathway analysis revealed that 228 genes were differentially expressed by benzene exposure, and cyp-35a2, pmk-1, and cep-1 were selected for further reproduction and multiparametric behavior analysis. Mutant analysis showed that benzene induced reproduction decline was rescued in cyp-35a2(gk317) mutant, whereas it was significantly exacerbated in pmk-1(km25) mutant, compared with the wildtype. The multiparametric behavior analysis on the mutants of selected genes revealed that each strain exhibits different response patterns, particularly, enhanced linear movement in the cyp-35a2(gk317) mutant, whereas the changes in partial body movement were observed in the pmk-1(km25) mutant by benzene exposure. A self-organizing map revealed that the pmk-1(km25) mutant group was the most densely clustered and located on the opposite side of the map of the cyp-35a2(gk317) mutant, each crossing that of the wildtype. Overall results suggest distinct roles of cyp-35a2 and pmk-1 genes in benzene-induced alterations in behavior and reproduction in C. elegans. This study also suggests computational behavior analysis is a suitable tool for addressing the integrative impact of chemical stress alongside with toxicogenomic approach.