Profiling antibiotic resistance genes (ARGs) in the Yellow River of China’s Henan Province is essential for understanding the health risks of antibiotic resistance. The profiling of ARGs was investigated using high-throughput qPCR from water samples in seven representative regions of the Yellow River. The absolute and relative abundances of ARGs and moble genetic elements (MGEs) were higher in summer than in winter (ANOVA,
p
< 0.001). The diversity and abundance of ARGs were higher in the Yellow River samples from PY and KF than the other sites. Temperature (
r
= 0.470 ~ 0.805,
p
< 0.05) and precipitation (
r
= 0.492 ~ 0.815,
p
< 0.05) positively influenced the ARGs, while pH had a negative effect (
r
= − 0.462 ~ − 0.849,
p
< 0.05). Network analysis indicated that the pathogenic bacteria
Rahnella
,
Bacillus
, and
Shewanella
were the possible hub hosts of ARGs, and
tnpA1
was the potential MGE hub. These findings provide insights into the factors influencing ARG dynamics and the complex interaction among the MGEs, pathogenic bacteria and environmental parameters in enriching ARGs in the Yellow River of Henan Province.