Malaria is a severe public health problem in the Amhara region, Ethiopia. A retrospective study was conducted to model and interpret the effects of climate variability and environmental factors on the monthly malaria surveillance data of 152 districts in the region. The data were analyzed using the Bayesian generalized Poisson spatiotemporal model. Malaria incidence had significant seasonal, temporal, and spatial variations in the region. The risk of malaria incidence was decreased by 24% per 100 m increase in altitude. Monthly minimum temperature decreases the risk of malaria by 2.2% per a 1 °C increment. The risk of malaria transmission was increased by 8% per 100 mm rise in the total monthly rainfall of districts. Besides, long-lasting insecticidal net coverage significantly reduces malaria risk by a factor of 0.8955. The finding suggests that malaria transmission was higher in northern and western districts. Hence, concerned bodies should consider seasonal, temporal, and spatial variations and effects of climate and environmental factors for intervention and elimination.