Staphylococcus aureus is a major pathogen, and its treatment is complicated by increasing multi-drug resistance. This bacterium’s propensity for intracellular survival presents a further challenge, with significant evidence suggesting S. aureus can hijack phagocytes for host dissemination leading to worse clinical outcome. Host pathways that facilitate intracellular survival in phagocytes remain unclear. To identify novel therapeutic targets engaged by S. aureus to survive intracellularly within primary human neutrophils, a multiplex gene expression analysis was performed using the Nanostring nCounter platform and RNA isolated from neutrophils harboring viable intracellular S. aureus. Pathway analysis revealed upregulation of multiple host pathways, the most significantly being cytokine and growth factor signaling pathways. Among growth factor signaling associated genes, the anti-inflammatory adenosine receptor, Adora2a (A2A) was significantly upregulated along with several other genes related to A2A activation. A2A expression was confirmed to be significantly upregulated at the gene and protein level in neutrophils harboring intracellular S. aureus, 1h & 3h post infection. Importantly treatment with an Inhibitor of A2A, ZM 241385, significantly reduced intracellular survival of S. aureus within neutrophils and was associated with enhanced ROS and myeloperoxidase expression. A2A inhibition also enhanced neutrophil production of the pro-inflammatory cytokine IL-8 whilst limiting expression of the anti-inflammatory cytokine IL-10. Taken together, our work suggests that S. aureus targets A2A signaling to enhance intracellular survival in neutrophils by suppressing their effector functions and potentially skewing them towards a more anti-inflammatory phenotype and reveals a potential new therapeutic target to overcome the intracellular survival of S. aureus.