Previous studies on environmental antibiotics resistance genes (ARGs) have focused on the pollution sources such as wastewater treatment plants, aquaculture and livestock farms, etc. Few of them had addressed this issue in a regional scale such as river catchment. Hence, the occurrence and abundances of 23 ARGs were investigated in surface water samples collected from 38 sites which located from the river source to estuary of the Beijiang River. Among them, 11 ARGs were frequently detected in this region and 5 ARGs (sulI, sulII, tetB, tetC, and tetW) were selected for their distribution pattern analysis. The abundances of the selected ARGs were higher in the upstream (8.70 × 106 copies/ng DNA) and downstream areas (3.17 × 106 copies/ng DNA) than those in the midstream areas (1.23 × 106 copies/ng DNA), which was positively correlated to the population density and number of pollution sources. Pollution sources of ARGs along the Beijiang River not only had a great impact on the abundances and diversity, but also on the distribution of specific ARGs in the water samples. Both sulI and sulII were likely originated from aquaculture farms and animal farms, tetW gene was possibly associated with the mining/metal melting industry and the electric waste disposal and tetC gene was commonly found in the area with multiple pollution sources. However, the abundance of tetB was not particularly related to anthropogenic impacts. These findings highlight the influence of pollution sources and density of population on the distribution and dissemination of ARGs at a regional scale.