Climate is one of the main limiting factors for agricultural productivity, where climate change may increase the risk for food production. Based on that, the aim of this study was to evaluate the impacts of climate change on rainfed and irrigated soybean yield in the MATOPIBA region, the new agricultural frontier in Brazil. The DSSAT CSM-CROPGRO-Soybean was used to simulate rainfed and irrigated yield using local soils, sowing dates, and maturity groups. The simulations included the baseline (1980–2010), and two future scenarios (2011–2040 and 2041–2070) for two representative concentration pathways (RCP 2.6 and 8.5). The future climate scenarios were obtained from global climate models (HadGEM2-ES and CSIRO mk3-6–0). The baseline showed a median yield of 3907 kg ha−1 across the region, a value that increased to 4006 kg ha−1 in the RCP 8.5 in 2011–2040. For the 2041–2070 period, RCPs 2.6 and 8.5 had a yield reduction to 3686 and 2388 kg ha−1, respectively. The average yield reduction was higher than 23% under RCP 8.5 (2041–2070), reaching more than 53% in some areas. The yield impact in future climate scenarios was related to rainfall reduction by 300–400 mm cycle−1, and temperature increased above 3 °C. The irrigation showed potential to offset negative climate change impacts, where yield gain was 2400 kg ha−1 under RCP 8.5. The future climate impact can be reduced by moving soybean crops preferentially to areas of higher altitude, with lower air temperature associated with irrigation. Further studies could explore potential adaptations related with physiological traits and crop management.