Mosquito-borne viruses encompass a wide range of pathogens, such as dengue and Zika viruses, that often cocirculate geographically. These viruses affect hundreds of millions of people worldwide, yet no clinically approved therapy is currently available for treating these viral infections. Thus, innovative therapies, especially inhibitors with broad antiviral activities against all these viruses, are urgently needed. While traditional therapeutic strategies mainly focus on inhibiting viral replication in a "one lock, one key" manner (e.g., viral protease and polymerase inhibitors), inhibitors targeting virions have recently emerged as a promising approach to achieve broad antiviral activities. Within this approach, Lipid Envelope Antiviral Disruption (LEAD) molecules were shown to broadly inhibit mosquito-borne viruses and other lipid membrane-enveloped viruses. Several LEAD molecules have been demonstrated to act against viral membranes in vitro, some of which have even shown in vivo efficacy to treat mosquito-borne viral infections. This therapeutic potential is further enhanced by molecular engineering to improve the inhibitors' pharmacological properties, laying the foundation for the LEAD antiviral strategy to be explored for possible treatment of mosquito-borne viral infections.