Suspended sediment concentration (SSC) is an important indicator of water quality that affects the biological processes of river ecosystems and the evolution of floodplains and river channels. The in situ SSC measurements are costly, laborious and spatially discontinuous, while the spaceborne SSC overcome these drawbacks and becomes an effective supplement for in situ observation. However, the spaceborne SSC observations of rivers are more challenging than those of lakes and reservoirs due to their narrow widths and the broad range of SSCs, among other factors. We developed a novel SSC retrieval method that is suitable for the rivers. Water was classified as clear or turbid based on the Forel–Ule index, and optimal SSC models were constructed based on the spectral responses to SSCs in cases of different turbidity. The estimated SSC had a strong correspondence with in situ measurements, with a root mean squared error (RMSE) of 24.87 mg/L and a mean relative error (MRE) of 51.91%. Satellite-derived SSC showed good consistency with SSCs obtained from gauging stations (r2 > 0.79). We studied the spatiotemporal variation in SSC in the Yangtze main stream from 2017 to 2021. It increased considerably from May to October each year, with the peak generally occurring in July or August (ca. 200–300 mg/L in a normal year and 800–1000 mg/L in a flood year), while it remained stable and decreased to around 50 mg/L from November to April of the following year. It was high in the east and low in the west, with local maxima in Chongqing (ca. 80–150 mg/L) and in the lower Dongting Lake reaches (ca. 80–100 mg/L) and a local minima in the downstream of the Three Gorges Dam (ca. 1–20 mg/L). Case studies in the Yibin reach and Three Gorges Reservoir determined that local variation in SSCs is due to special hydrodynamic conditions and anthropogenic activities. The procedure applied to process Sentinel-2 imagery and the novel SSC retrieval method we developed supplement the deficiencies in river SSC retrieval.