Here we introduce a new endpoint ″census population size″ to evaluate the epidemiology and control of infections, where the parasite, rather than the infected human host, is the unit of measurement. To calculate census population size, we rely on a definition of parasite variation known as multiplicity of infection (MOI ), based on the hyper-diversity of the multigene family. We present a Bayesian approach to estimate MOI from sequencing and counting the number of unique DBLα tags (or DBLα types) of genes, and derive from it census population size by summation of MOI in the human population. We track changes in this parasite population size and structure through sequential malaria interventions by indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC) from 2012 to 2017 in an area of high-seasonal malaria transmission in northern Ghana. Following IRS, which reduced transmission intensity by > 90% and decreased parasite prevalence by ~40-50%, significant reductions in diversity, MOI , and population size were observed in ~2,000 humans across all ages. These changes, consistent with the loss of diverse parasite genomes, were short lived and 32-months after IRS was discontinued and SMC was introduced, diversity and population size rebounded in all age groups except for the younger children (1-5 years) targeted by SMC. Despite major perturbations from IRS and SMC interventions, the parasite population remained very large and retained the population genetic characteristics of a high-transmission system (high diversity; low repertoire similarity) demonstrating the resilience of to short-term interventions in high-burden countries of sub-Saharan Africa.