BACKGROUND: Long-lasting insecticidal nets and indoor residual sprays have significantly reduced the burden of malaria. However, several hurdles remain before elimination can be achieved: mosquito vectors have developed resistance to public health insecticides, including pyrethroids, and have altered their biting behaviour to avoid these indoor control tools. Systemic insecticides, drugs applied directly to blood hosts to kill mosquitoes that take a blood meal, offer a promising vector control option. To date, most studies focus on repurposing ivermectin, a drug used extensively to treat river blindness. There is concern that overdependence on a single drug will inevitably repeat past experiences with the rapid spread of pyrethroid resistance in malaria vectors. Diversifying the arsenal of systemic insecticides used for mass drug administration would improve this strategy's sustainability. METHODS: Here, a review was conducted to identify systemic insecticide candidates and consolidate their pharmacokinetic/pharmacodynamic properties. The impact of alternative integrated vector control options and different dosing regimens on malaria transmission reduction are illustrated through mathematical model simulation. RESULTS: The review identified drugs from four classes commonly used in livestock and companion animals: avermectins, milbemycins, isoxazolines and spinosyns. Simulations predicted that isoxazolines and spinosyns are promising candidates for mass drug administration, as they were predicted to need less frequent application than avermectins and milbemycins to maintain mosquitocidal blood concentrations. CONCLUSIONS: These findings will provide a guide for investigating and applying different systemic insecticides to achieve more effective and sustainable control of malaria transmission.