[Objective] The spatiotemporal variation characteristics of chemical fertilizer use in the Yellow River basin and its relationship with grain production were analyzed in order to provide a theoretical basis for the control of chemical fertilizer application in the basin. [Methods] Fertilizer application and grain yield data in the Yellow River basin from 2000 to 2021 were used with spatial autocorrelation analysis, kernel density analysis, and ellipse of standard deviation to analyze the temporal and spatial variation characteristics of fertilizer use in the Yellow River basin, and to explore the relationship between fertilizer use and grain yield. [Results] From 2000 to 2021, grain yield in the Yellow River basin has increased by 49.55%, which was greater than the growth rate of chemical fertilizer application (24.87%). After 2013, chemical fertilizer applications in the basin began to fluctuate and decrease, while grain yield still maintained a growth trend. The efficiency of fertilizer application has significantly improved. During the past 22 years, the regional agglomeration trend of chemical fertilizer application in the Yellow River basin has been continuously weakening. The amount of chemical fertilizer use in the Yellow River basin has a certain degree of spatial imbalance, with hot areas mainly concentrated in Henan and Shandong Province, and cold areas concentrated in Qinghai and Gansu Province. During the past 22 years, the number of hot areas of chemical fertilizer use in the Yellow River basin has decreased, high-value aggregation areas have moved westward, and cold areas have increased. During the past 22 years, the use of chemical fertilizers in the upper, middle, and lower reaches of the Yellow River basin has increased by 46.52%, 38.68%, and 9.5%, respectively. The rapid growth of chemical fertilizer use in the western region has moved the center of gravity of chemical fertilizer use in the basin 57.40 km to the northwest. During the past 22 years, the center of gravity of grain production in the Yellow River basin has shifted 22.06 km to the northwest, and it has tended to separate from the center of gravity of fertilizer use. [Conclusion] The action of reducing chemical fertilizer use and increasing fertilizer use efficiency in the Yellow River basin has achieved significant results, but the overall intensity of chemical fertilizer use still exceeds the standard. Therefore, it will still be necessary to reduce chemical fertilizer use in the future.