Many studies have been published on the use of models to assess water quality through faecal contamination levels. However, the vast majority of this work has been conducted in developed countries and similar studies from developing countries in tropical regions are lacking. Here, we used the Seneque/Riverstrahler model to investigate the dynamics and seasonal distribution of total coliforms (TC), an indicator of faecal contamination, in the Red River (Northern Vietnam) and its upstream tributaries. The results of the model showed that, in general, the overall correlations between the simulated and observed values of TC follow a 1:1 relationship at all examined stations. They also showed that TC numbers were affected by both land use in terms of human and livestock populations and by hydrology (river discharge). We also developed a possible scenario based on the predicted changes in future demographics and land use in the Red River system for the 2050 horizon. Interestingly, the results showed only a limited increase of TC numbers compared with the present situation at all stations, especially in the upstream Vu Quang station and in the urban Ha Noi station. This is probably due to the dominance of diffuse sources of contamination relative to point sources. The model is to our knowledge one of the first mechanistic models able to simulate spatial and seasonal variations of microbial contamination (TC numbers) in the whole drainage network of a large regional river basin covering both urban and rural areas of a developing country.