Although dog-mediated rabies poses a significant public health and economic burden in Ethiopia, the spatiotemporal epidemiology of the disease remains poorly defined and understood. The objective of this study was to explore the spatiotemporal dynamics and identify possible risk factors for dog-mediated human rabies in the Amhara region of Northwest Ethiopia. A retrospective time-series ecological study was employed on dogmediated human rabies in Northwest Ethiopia. The study utilized time-series rabies surveillance data collected in the Amhara region between January 2016 and December 2023. Descriptive epidemiological analysis, spatial statistics (including choropleth mapping, GetisOrd Gi* hot spot detection, Moran’s I spatial autocorrelation, and Kulldorff’s space-time scan statistics), and negative binomial regression models were employed to examine incidence trends, identify cluster formations, and assess associated environmental and demographic risk factors. Among 14159 reported dog-mediated human rabies cases, the annual incidence rate ranged from 2.75 to 14.12 per 100,000 population, with a mean of 7.34 and a median of 6.78 over the study period. The overall trend indicated an increasing trend in rabies cases from 2016 up to around mid-2022, peaking between late 2022 and early 2023. The temporal trend showed relative stability in incidence rates between 2016 and 2017 (IR=4.99 to 5.17), with a significant decline in 2018 and a sharp rise from 2020 to 2022 (IR=9.27 to 14.12), and a drop in 2023 (IR=8.39). Seasonal decomposition indicated peaks of cases in summer and autumn. The spatial analysis revealed that the Bahir Dar Special Zone was the most significant hotspot from 2020–2023 with an incidence risk (IR) of 168.65 and a space-time cluster relative risk (RR) of 65.12. Persistent hot spots were detected in the North Gondar zone in 2016, 2020, and 2022 (p < 0.05) and East Gojam zone in 2021, 2022 (p < 0.05) and in 2023 (p < 0.01). Significant spatial autocorrelation of the incidence of cases was also identified in the region in the year 2020 (Moran’s I=0.36, P < 0.05) and 2023 (Moran’s I=0.52, P < 0.01). Negative binomial regression revealed a positive association of rabies incidence in the zones with higher population density, incidence rate ratio (IRR=1.004), temperature (IRR=1.217), and precipitation (IRR=1.001), while dog vaccination coverage was negatively associated (IRR=0.905, p<0.001). Significant risk variation was observed across zones, with the Bahir Dar Special Zone (IRR=2.13) showing the highest risk. In conclusion, this study revealed that dog-mediated human rabies remains a public health threat in Northwest Ethiopia, characterized by pronounced spatiotemporal, seasonal, and geographic heterogeneity. Therefore, multidisciplinary and targeted interventions using a One Health approach are essential to reduce and ultimately eliminate dog-mediated rabies in the study area.