Striga hermonthica infestation and recurrent drought are major constraints to sorghum production in sub-Saharan Africa, significantly reducing both grain yield and nutritional quality. Developing sorghum varieties that combine resistance to Striga with enhanced nutritional traits is therefore a priority for food security and sustainable agriculture. This study investigated the genetic basis of Striga resistance and nutritional composition in 75 diverse sorghum genotypes, including advanced breeding lines and released varieties from Zimbabwe and South Africa. Whole-genome sequencing of genomic DNA from these genotypes was performed to identify single-nucleotide polymorphisms (SNPs) associated with secondary metabolites and macronutrient traits. SNPs linked to the biosynthesis of key phenolic acids—including hydroxybenzoic, gallic, ferulic, cinnamic, p-coumaric, caffeic, protocatechuic, and syringic acids—were distributed across multiple chromosomes, with chromosome 1 exhibiting the highest density of associated SNPs. Manhattan plot analyses highlighted significant associations for caffeic acid on chromosomes 1 and 9, protocatechuic acid on chromosomes 2, 3, 4, 5, and 10, and syringic acid on chromosomes 3, 5, 8, 9, and 10. Similarly, SNPs associated with macronutrient composition—including ash, carbohydrate, fat, fibre, and protein—were identified on chromosomes 1, 3, 4, 8, and 9. Several genomic regions were found to potentially exert pleiotropic effects, influencing both Striga resistance and nutritional traits, indicating co-localized genetic control. These findings provide a detailed map of key genomic regions underlying resilience and dietary quality in sorghum. The identified SNP markers can serve as valuable tools for marker-assisted selection, enabling the development of sorghum varieties that are both Striga-tolerant and nutritionally enhanced. By integrating resistance and nutritional profiling at the genomic level, this study contributes to the advancement of sorghum breeding strategies aimed at improving food security and nutritional outcomes in stress-prone environments of sub-Saharan Africa.