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Vector control with insecticides is an important preventive measure against mosquito-borne infectious diseases, such as malaria and dengue. The intensive usage of few insecticides has resulted in emerging resistance in mosquitoes, and unwanted off-target toxic effects. Therefore, there is great interest in alternative active ingredients. Here, we explore indole-based compounds as selective inhibitors against acetylcholinesterase 1 (AChE1) from the disease-transmitting mosquitoes Anopheles gambiae (An. gambiae, AgAChE1) and Aedes aegypti (Ae. aegypti, AeAChE1) as potential candidates for future insecticides used in vector control. Three sets of compounds were designed to explore their structure–activity relationship, and investigate their potentials regarding potency and selectivity. 26 indole-based compounds were synthesized and biochemically evaluated for inhibition against AgAChE1, AeAChE1, and human AChE (hAChE). The compounds were shown to be potent inhibitors against AChE1, and selective for AChE1 over hAChE. N-Methylation of the indole moiety clearly increased the inhibition potency, and a bulkier benzyl moiety improved the selectivity. X-ray crystallography shows that the inhibitors bind at the bottom of the active site gorge of mouse AChE (mAChE), while molecular dynamics simulations revealed different binding poses in mAChE and AgAChE1. Four potent and selective inhibitors were subjected to in vivo mosquito testing. Topical application showed strong insecticidal effects on An. gambiae and Ae. aegypti, highlighting this compound class as an interesting alternative for future insecticide research.