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Background  Sorghum yields in sub-Saharan Africa (SSA) are greatly reduced by parasitic plants of the genus  Striga  (witchweed). Vast global sorghum genetic diversity collections, as well as the availability of modern sequencing technologies, can be potentially harnessed to effectively manage the parasite.    Results  We used laboratory assays – rhizotrons to screen a global sorghum diversity panel to identify new sources of resistance to  Striga ; determine mechanisms of resistance, and elucidate genetic loci underlying the resistance using genome-wide association studies (GWAS). New  Striga  resistant sorghum determined by the number, size and biomass of parasite attachments were identified. Resistance was by; i) mechanical barriers that blocked parasite entry, ii) elicitation of a hypersensitive reaction that interfered with parasite development, and iii) the inability of the parasite to develop vascular connections with hosts. Resistance genes underpinning the resistance corresponded with the resistance mechanisms and included pleiotropic drug resistance proteins that transport resistance molecules; xylanase inhibitors involved in cell wall fortification and hormonal regulators of resistance response, Ethylene Response Factors.    Conclusions  Our findings are of fundamental importance to developing durable and broad-spectrum resistance against  Striga  and have far-reaching applications in many SSA countries where  Striga  threatens the livelihoods of millions of smallholder farmers that rely on sorghum as a food staple.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12870-021-03155-7.

GWAS provides biological insights into mechanisms of the parasitic plant (Striga) resistance in sorghum