Malaria elimination and eradication efforts have stalled globally. Further, asymptomatic infections as silent transmission reservoirs are considered a major challenge to malaria elimination efforts. There is increased interest in a mass screen-and-treat (MSAT) strategy as an alternative to mass drug administration to reduce malaria burden and transmission in endemic settings. This study systematically synthesized the existing evidence on MSAT, from both epidemiological and economic perspectives. Searches were conducted on six databases (PubMed, EMBASE, CINALH, Web of Science, Global Health, and Google Scholar) between October and December 2020. Only experimental and quasi-experimental studies assessing the effectiveness and/or cost-effectiveness of MSAT in reducing malaria prevalence or incidence were included. Of the 2,424 citation hits, 14 studies based on 11 intervention trials were eligible. Eight trials were conducted in sub-Saharan Africa and three trials in Asia. While five trials targeted the community as a whole, pregnant women were targeted in five trials, and school children in one trial. Transmission setting, frequency, and timing of MSAT rounds, and measured outcomes varied across studies. The pooled effect size of MSAT in reducing malaria incidence and prevalence was marginal and statistically nonsignificant. Only one study conducted an economic evaluation of the intervention and found it to be cost-effective when compared with the standard of care of no MSAT. We concluded that the evidence for implementing MSAT as part of a routine malaria control program is growing but limited. More research is necessary on its short- and longer-term impacts on clinical malaria and malaria transmission and its economic value.