Expansion of CAG trinucleotide repeats within open reading frame causes the protein to gain toxic properties resulting in dysfunction and degeneration of specific subpopulation of neurons in the brain. Hippo pathway regulates cell number by cell proliferation or cell death by regulating Yorkie, which is the major downstream target of Hippo pathway. Yorkie in turn, when activated leads to activation of cyclin E, microRNA bantam and apoptosis inhibitor diap1 which are involved in cell proliferation and apoptosis. Here, we show that Yorkie is robust genetic modifier of polyQ mediated neurodegeneration. Overexpression of Yorkie in polyQ background reduces the severity of pathogenecity caused by inclusion bodies while downregulation has the opposite effect. Yorkie suppresses cytotoxic effect of polyQ by Cyclin E and bantam but does not show significant rescue by Diap1, suggesting that apoptotic pathway is not involved. PolyQ inclusion bodies causes overexpression of Antimicrobial peptides in neurons by activating the Nuclear Factor-κB (NF-κB) transcription factor Relish, a key activator of IMD pathway. We show upregulation of Yorkie downregulates expression of Relish and other components of Toll and IMD pathway in eye imaginal disc. Downregulation of antimicrobial peptides significantly rescues polyQ phenotypes. Finally we show that polyQ interacts with Yorkie to modulate its functions making it a strong genetic modifier of polyQ mediated neurodegeneration by regulating cell cycle genes and innate immune response. .