Phosphoinositide 3-kinase gamma isoform (PI3K|γ) plays a vital role in myeloid-derived cells from the immunosuppressive tumor microenvironment. IPI-549, a lately discovered small molecule selective PI3K|? inhibitor, is presently under immuno-oncology numerous studies in conjunction with nivolumab, an anti-PD-1 monoclonal antibody immune checkpoint blocker. The objective of this research would be to investigate whether IPI-549 could reverse P-glycoprotein (P-gp)-mediated MDR when coupled with chemotherapeutic substrates of P-gp. Cytotoxicity assays demonstrated that IPI-549 reverses P-gp-mediated MDR in SW620/Ad300 and LLC-PK-MDR1 cells. IPI-549 increases the quantity of intracellular paclitaxel and inhibits the efflux of paclitaxel from SW620/Ad300 cells. ABCB1-ATPase assay demonstrated that IPI-549 energizes the activity of ABCB1-ATPase. IPI-549 doesn’t affect the expression and doesn’t modify the subcellular localization of P-gp in SW620/Ad300 cells. The mixture of IPI-549 with paclitaxel demonstrated that IPI-549 potentiates the anti-tumor results of paclitaxel in P-gp-overexpressing MDR SW620/Ad300 xenograft tumors. With numerous studies starting to add recently approved immune checkpoint-based immunotherapy into standard-of-care immunogenic chemotherapy to enhance patient outcomes, our findings offer the rationale of adding IPI-549 to both chemotherapeutic and immunotherapeutic facets of cancer combination treatment strategies.