Background <p>Volatile pyrethroid spatial repellents (VPSRs) have emerged as promising complementary tools for vector control. This systematic review and meta-analysis evaluated the protective efficacy (PE) of VPSRs against mosquito- and sand-fly-borne human infections, and against vector numbers in traps.</p> Methods <p>Clinical infection and entomological studies that evaluated VPSRs against human infection with <i>Plasmodium</i>, arboviruses (Dengue and Zika), and <i>Leishmania</i>, and against their respective vectors, were systematically reviewed. Random-effects meta-analyses estimated pooled PE values and explored moderators including vector trapping method, deployment setting (indoor/outdoor), and active ingredient (a.i.) concentration.</p> Results <p>A total of 49 VPSR studies containing 154 datasets met the inclusion criteria, comprising 6 trials (7 datasets) against human infection incidence, and 43 entomological studies mostly of mosquitoes (147 datasets); 73.5% tested active ingredients transfluthrin and 22.4% tested metofluthrin.</p> <p>Pooled estimates from transfluthrin VPSR trials indicated protective effects of 50% (95% CI 21–69%) against <i>Plasmodium</i> (<i>n</i> = 3) and 34% (95% CI 10–52%) against arboviruses (Dengue and Zika, <i>n</i> = 1). Evidence for <i>Leishmania</i> infection incidence was limited to a single trial (PE = 48%, 95% CI 26–63%). Metofluthrin showed no effect against <i>Plasmodium</i> (<i>n</i> = 1).</p> <p>Exposure to VPSRs was associated with substantial reductions in trapped mosquito and sand fly numbers. The comparative protection inferred from the entomological data was variably dependent on trap type: the mosquito data gave pooled mean PE values of 57–62% by human landing catches; 35–55% using Centers for Disease Control light traps (CDC-LT); and 47–88% using CDC-LT co-located with sources of CO². The wider range of pyrethroid compounds tested against <i>Phlebotomus</i> sand flies (<i>n</i> = 4) gave trap-specific PE values of 93%, 53%, and 78%, respectively. VPSR deployment in outdoor settings appeared not to be generally inferior to indoor deployment, and efficacy values tended not to differ significantly between mosquito genera. The relationship between the level of repellency (and/or lethality) and VPSR a.i. concentration is not clear, though higher concentrations (≥ 20% w/v transfluthrin or metofluthrin) appeared to be less effective.</p> Conclusions <p>The collective results demonstrate that transfluthrin-based VPSRs were associated with reduced vector numbers and reduced <i>Plasmodium</i> infection incidence, with likely effectiveness also against arboviral and <i>Leishmania</i> infection incidence. However, existing evidence for reduced infection incidence is very limited despite strong entomological effects. More studies to evidence-base and strengthen conclusions are needed on many key aspects of VPSR products for programmatic and sustainable scale-up.</p>