Indoor residual spraying (IRS) with insecticide is now recommended for malaria control in high-transmission settings. However, concerns about insecticide resistance have increased. We conducted a cross-sectional household survey in high-transmission northern Uganda in two districts previously sprayed with pyrethroids before documentation of pyrethroid resistance and at least one round of carbamates and in one contiguous district that was not sprayed. Parasitemia prevalence among children < 5 years of age was lower in the two IRS districts compared with the non-sprayed district: 37.0% and 16.7% versus 49.8%, P < 0.001. Anemia prevalence was also significantly lower in the two IRS districts: 38.8% and 36.8% versus 53.0%, P < 0.001. Multivariable Poisson regression models indicated that a child living in a sprayed district had a 46% and 32% lower risk of parasitemia and anemia, respectively, than a child in a non-sprayed district (P < 0.001). Carefully managed IRS can significantly reduce malaria burden in high-transmission settings.