Abstract: Mosquito-borne diseases pose a significant global health threat, necessitating novel vector control strategies. This study explores the potential of harnessing the host immunity against mosquitoes through vaccination. Using Culex pipiens (C. pipiens) as the study model, we found polyclonal antibodies against C. pipiens abdomen significantly compromised the mosquito oviposition and increased mosquito mortality, primarily through the classical complement activation pathway. However, repeated exposure led to resistance, indicating potential adaptation. Proteomic analysis identified metabolic proteins as key targets, with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighting their roles in carboxylic acid metabolism, tyrosine degradation, and proteasome pathways. Intriguingly, cross-species reactivity was confirmed via Western blot, showing strong binding of Culex-specific antibodies to Anopheles and Aedes abdominal proteins. This study provides mechanistic insights into antibody-based mosquito suppression, highlighting its feasibility as a novel vector control strategy while underscoring the need for further research on resistance management and ecological impacts.