AbstractRandomized controlled trials have established that seasonal malaria chemoprevention (SMC) in children is a promising strategy to reduce malaria transmission in Sahelian West Africa. This strategy was recently introduced in a dozen countries, and about 12 million children received SMC in 2016. However, evidence on SMC effectiveness under routine programme conditions is sparse. We aim to measure the effects of the nationwide SMC programme in Mali on the prevalence of malaria and anemia in children 6–59 months. We used data from the 2015 nationally representative malaria indicator survey. A post-test only with non-randomized control group study was designed. We fitted a generalized structural equation model that controlled for potential bias on observed and non-observed variables (endogenous treatment effect model). Having received SMC reduced by 44% (95% CI [0.39–0.49]) the risk of having a positive rapid diagnostic test for malaria. In addition, the programme indirectly reduced by 18% the risk of moderate-to-severe anemia (95% CI [0.15–0.21]). SMC in Mali has substantial protective effects under routine nationwide programme conditions. Endogenous treatment effects analyses can contribute to rigorously measuring the effectiveness of health programmes and to bridging a widening gap in evaluation methods to measure progress towards achieving malaria elimination.