Background: Although malaria control investments worldwide have resulted in dramatic declines in transmission since 2000, progress has stalled. In the Amazon, malaria resurgence has followed withdrawal of Global Fund support of the Project for Malaria Control in Andean Border Areas (PAMAFRO). We estimate intervention-specific and spatially-explicit effects of the PAMAFRO program on malaria incidence across the Loreto region of Peru, and consider the influence of the environmental risk factors in the presence of interventions. Methods: We conducted a retrospective, observational, spatial interrupted time series analysis of malaria incidence rates among people reporting to health posts across Loreto, Peru between the first epidemiological week of January 2001 and the last epidemiological week of December 2016. Model inference is at the smallest administrative unit (district), where the weekly number of diagnosed cases of Plasmodium vivax and Plasmodium falciparum were determined by microscopy. Census data provided population at risk. We include as covariates weekly estimates of minimum temperature and cumulative precipitation in each district, as well as spatially- and temporally-lagged malaria incidence rates. Environmental data were derived from a hydrometeorological model designed for the Amazon. We used Bayesian spatiotemporal modeling techniques to estimate the impact of the PAMAFRO program, variability in environmental effects, and the role of climate anomalies on transmission after PAMAFRO withdrawal. Findings: During the PAMAFRO program, incidence of P. vivax declined from 42.8 to 10.1 cases/1000 people/year. Incidence for P. falciparum declined from 14.3 to 2.5 cases/1000 people/year over this same period. The effects of PAMAFRO-supported interventions varied both by geography and species of malaria. Interventions were only effective in districts where interventions were also deployed in surrounding districts. Further, interventions diminished the effects of other prevailing demographic and environmental risk factors. Withdrawal of the program led to a resurgence in transmission. Increasing minimum temperatures and variability and intensity of rainfall events from 2011 onward and accompanying population displacements contributed to this resurgence. Interpretation: Malaria control programs must consider the climate and environmental scope of interventions to maximize effectiveness. They must also ensure financial sustainability to maintain local progress and commitment to malaria prevention and elimination efforts, as well as to offset the effects of environmental change that increase transmission risk. Funding: National Aeronautics and Space Administration, National Institutes of Health, Bill and Melinda Gates Foundation. © 2023 The Author(s)