In malaria-endemic countries in Africa, a large proportion of child deaths are directly or indirectly attributable to infection with Plasmodium falciparum. Four years after high coverage, multiple malaria control interventions were introduced on Bioko Island, Equatorial Guinea, changes in infection with malarial parasites, anemia, and fever history in children were estimated and assessed in relation to changes in all-cause under-5 mortality. There were reductions in prevalence of infection (odds ratio [OR] = 0.31, 95% confidence interval [CI] = 0.2-0.46), anemia (OR = 0.11, 95% CI = 0.07-0.18), and reported fevers (OR = 0.41, 95% CI = 0.22-0.76) in children. Under-5 mortality fell from 152 per 1,000 births (95% CI = 122-186) to 55 per 1,000 (95% CI = 38-77; hazard ratio = 0.34 [95% CI = 0.23-0.49]). Effective malaria control measures can dramatically increase child survival and play a key role in achieving millennium development goals.