Sea Surface Salinity (SSS) is a key variable in physical oceanography and biogeochemical research. Microwave remote sensing technology has been used to monitor SSS in open ocean areas. However, the limited spatial resolution and suboptimal precision exhibited by microwave remote sensing derived SSS data have led to the omission of crucial oceanic information, consequently constraining its utilization. In this study, an artificial neural network (ANN) model for the regional SSS inversion was constructed utilizing in situ SSS measurements in the northern South China Sea and remote sensing sea surface temperature and reflectance at wavelengths of 412, 443, 488, 555 and 667 nm derived from MODIS-Aqua satellite Level 2 data. The model showed a good performance of root mean square error (RMSE) of 0.32 and 0.34 for the model training and testing datasets, with mean bias (MB) of 0 and 0.01, and correlation coefficients (R2) reaching 0.93. The model validation indicated that the ANN model reproduced the spatial distribution of SSS highly consistent with the measured SSS (RMSE = 2.75, MB = −1.67, R2 = 0.95), demonstrating its strong applicability in the NSCS. In contrast to other local SSS inversion models, our ANN model clearly showed the fine-scale SSS feature under the intrusion of Pearl River plume near to Dongsha Island with the help of anticyclonic-cyclonic eddies. This prediction closely aligned with the observations from the Soil Moisture Active Passive SSS dataset. The ANN model was applied to MODIS-Aqua data to generate the monthly SSS from 2003 to 2022. A decreasing SSS trend in SSS of 0.02 psu y−1 during 2005–2013 and 2017–2020 and a slightly increasing SSS trend of 0.01 psu y−1 from 2013 to 2017 were observed. Further analysis shows the low-frequency variability of SSS is significantly correlated with the Pacific Decadal Oscillation.