Background: In central Senegal malaria incidences have declined in recent years in response to scaling-up of control measures, but now remains stable, making elimination improbable. Additional control measures are needed to reduce transmission. Methods: By using a meta-population mathematical model, we evaluated chemotherapy interventions targeting stable malaria hotspots, using a differential equation framework and incorporating human mobility, and fitted to weekly malaria incidences from 45 villages, over 5 years. Three simulated approaches for selecting intervention targets were compared: a) villages with at least one malaria case during the low transmission season of the previous year; b) villages ranked highest in terms of incidence during the high transmission season of the previous year; c) villages ranked based on the degree of connectivity with adjacent populations. Results: Our mathematical modeling, taking into account human mobility, showed that the intervention strategies targeting hotspots should be effective in reducing malaria incidence in both treated and untreated areas. Conclusions: Mathematical simulations showed that targeted interventions allow increasing malaria elimination potential.