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Soil organic carbon (SOC) is a critical indicator for the global carbon cycle and the overall carbon pool balance. Obtaining soil maps of surface SOC is fundamental to evaluating soil quality, regulating climate change, and global carbon cycle modeling. However, efficient approaches for obtaining accurate SOC information remain challenging, especially in remote or inaccessible regions of the Qinghai–Tibet Plateau (QTP), which is influenced by complex terrains, climate change, and human activities. This study employed field measurements, SoilGrids250m (SOC_250m, a spatial resolution of 250 m × 250 m), and Sentinel-2 images with different machine learning methods to map SOC content in the QTP. Four machine learning methods including partial least squares regression (PLSR), support vector machines (SVM), random forest (RF), and artificial neural network (ANN) were used to construct spatial prediction models based on 396 field-collected sampling points and various covariates from remote sensing images. Our results revealed that the RF model outperformed the PLSR, SVM, and ANN models, with a higher determination coefficient (R2 of 0.82 is from the training datasets) and the ratio of performance to deviation (RPD = 2.54). The selected covariates according to the variable importance in projection (VIP) were: SOC_250m, B2, B11, Soil-Adjusted Vegetation Index (SAVI), Normalized Difference Vegetation Index (NDVI), B5, and Soil-Adjusted Total Vegetation Index (SATVI). The predicted SOC map showed an overall decrease in SOC content ranging from 69.30 g·kg−1 in the southeast to 1.47 g·kg−1 in the northwest. Our prediction showed spatial heterogeneity of SOC content, indicating that Sentinel-2 images were acceptable for characterizing the variability of SOC. The findings provide a scientific basis for carbon neutrality in the QTP and a reference for the digital mapping of SOC in the alpine region. [ABSTRACT FROM AUTHOR]