Genetic underpinnings of host-pathogen interactions in the parasitic plant Striga hermonthica, a root parasitic plant that ravages cereals in sub-Saharan Africa, are unclear. We performed a comparative transcriptome study on five genotypes of sorghum exhibiting diverse resistance responses to S. hermonthica using weighted gene co-expression network analysis (WGCNA). We found that S. hermonthica elicits both basal and effector-triggered immunity - like a bona fide pathogen. Resistance response was genotype specific. Some resistance responses followed the salicylic acid-dependent signaling pathway for systemic acquired resistance characterized by cell wall reinforcements, lignification and callose deposition while in others the WRKY-dependent signaling pathway was activated leading to a hypersensitive response (HR). In some genotypes, both modes of resistance were activated while in others, either mode dominated the resistance response. Cell-wall-based resistance was common to all sorghum genotypes but strongest in IS2814, while HR-based response was specific to N13, IS9830 and IS41724. WGCNA further allowed for pinpointing of S. hermonthica resistance causative genes in sorghum. Some highlights include a Glucan synthase-like 10, a pathogenesis-related thaumatin-like family, and a phosphoinositide phosphatase gene. Such candidate genes will form a good basis for subsequent functional validation and possibly future resistance breeding.