Heavy metal stress threatens plant growth and productivity. In this study, we investigated the effects of CuSO4 and ZnSO4 toxicity on sorghum seedlings, focusing on their impact on biomass, germination rates, growth parameters, antioxidant enzyme activities, gene expression profiles, and stress resistance mechanisms. As a result, eight sorghum superoxide dismutase (SOD) genes were identified, and their evolutionary relationships with cis-acting regulatory elements and their expressional patterns were evaluated. Integrating transcriptomic data revealed a key SOD member SbCSD1 that might contribute to plant abiotic stress resistance. Furthermore, SbCSD1 overexpression enhanced plant tolerance to CuSO4 and ZnSO4 stress by regulating SOD activity and interacting with copper chaperone for superoxide dismutase 1 (CCS1) in the plant nucleus and cytoplasm. Meanwhile, silencing CCS1 in SbCSD1-overexpressing plants revealed that SbCSD1 and CCS1 synergistically contribute to Cu stress tolerance. By integrating transcriptomic and genetic data, herein we provide novel insights into the orchestration of plant responses to heavy-metal stress in sorghum by SOD.