Aedes aegypti is the primary mosquito vector of several human arboviruses including dengue virus (DENV). Vector control is the principal intervention to decrease the transmission of these viruses. The characterization of molecules involved in the mosquito physiological responses to blood-feeding may help to identify novel targets useful in the design of effective control strategies. In this study, we evaluated the in vivo effect of feeding adult female mosquitoes with human blood containing either heat-inactivated (IB), normal serum (NB), and RNA-seq based transcript expression was compared against sugar-fed (SF) mosquitoes. In the in vitro experiments, we treated Aag2 cells with a recombinant version of the complement proteins (hC3 or hC5a) and compared transcript expression to untreated control cells after 24h. The transcript expression analysis revealed that human complement proteins modulate approximately 2,300 transcripts involved in multiple biological functions, including the immune system. We also found 161 up-regulated and 168 down-regulated transcripts differentially expressed when hC3 and hC5a were compared against the control untreated cells. We conclude that active human complement induces significant changes in the transcriptome of Ae. aegypti mosquitoes, which can influence the infective capacity of pathogens ingested during blood meals.