Parasitic weeds of the Orobanchaceae family cause substantial economic losses and pose significant threats to global agriculture. However, management of such parasitism is challenging, and very few resistance genes have been cloned and characterized in depth. Here, we performed a genome-wide association study using 152 tomato accessions and identified SlABCG45 as a key gene that mediates host resistance to Phelipanche aegyptiaca by affecting the level of strigolactones (SLs) in root exudates. SLs are synthesized and released by host plants and act as germination stimulants for parasitic weeds. We found that SlABCG45 and its close homolog SlABCG44 were membrane-localized SL transporters with essential roles in exudation of SLs to the rhizosphere, resistance to Phelipanche and Orobanche, and upward transport of SLs from roots to shoots. As a predominant environmental stimulant exacerbates parasitism, phosphorus deficiency dramatically induced SlABCG45 expression and weakly induced SlABCG44 expression via the transcription factors SlNSP1 and SlNSP2. Knockout of SlABCG45 in tomato had little effect on yield traits in a broomrape-free field, but conferred increased resistance to different Phelipanche and Orobanche species, resulting in a ~30% yield increase in a Phelipanche-infested field. Our findings reveal that targeting a single gene by genome editing can confer broad-spectrum parasite resistance in tomato, providing an effective strategy for the sustainable control of parasitic plants in agriculture.