Drosophila suzukii is a pest of global concern due to its great impact on several crops. The entomopathogenic nematode Steinernema carpocapsae was highly virulent to the larvae of the fly although some immune mechanisms were triggered along the infection course. Thus, to understand the gene activation profile we performed a comparative transcriptome of D. suzukii larvae infected with S. carpocapsae and Xenorhabdus nematophila to map the differentially expressed genes involved in the defence response. The analysis exposed the induction of genes involved in the humoral response such as the antimicrobial peptides and pattern-recognition receptors while there was a suppression of the cellular defence. Besides, genes involved in melanisation, and clot formation were downregulated hindering the encapsulation response and wound healing. After the infection, larvae were in a stress condition with an enrichment of metabolic and transport functionalities. Concerning the stress response, we observed variations of the heat-shock proteins, detoxification, and peroxidase enzymes. These findings set a genetical comprehensive knowledge of the host-pathogen relation of D. suzukii challenged with S. carpocapsae which could support further comparative studies with entomopathogenic nematodes.