Reducing the human reservoir of malaria parasites is critical for elimination. We conducted a community randomized controlled trial in Southern Province, Zambia to assess the impact of three rounds of a mass test and treatment (MTAT) intervention on malaria prevalence and health facility outpatient case incidence using random effects logistic regression and negative binomial regression, respectively. Following the intervention, children in the intervention group had lower odds of a malaria infection than individuals in the control group (adjusted odds ratio = 0.47, 95% confidence interval [CI] = 0.24–0.90). Malaria outpatient case incidence decreased 17% in the intervention group relative to the control group (incidence rate ratio = 0.83, 95% CI = 0.68–1.01). Although a single year of MTAT reduced malaria prevalence and incidence, the impact of the intervention was insufficient to reduce transmission to a level approaching elimination where a strategy of aggressive case investigations could be used. Mass drug administration, more sensitive diagnostics, and gametocidal drugs may potentially improve interventions targeting the human reservoir of malaria parasites.