The PI3Kδ protein is an integral component of Phosphatidylinositol 3 kinase (PI3K) signaling in B lymphocytes necessary for their functions of proliferation and metabolism. Trypanosoma species utilize mechanisms targeted at evading host B cells and antibody responses which are critical for immunity. In this project, we sought to determine the impact of PI3Kδ in immunity to Trypanosoma congolense infection in mice. Infection of p110δD910A mutant mice with T.congolense show a surprisingly enhanced control of parasitemia in early infection (7-9 days post-infection), when compared with the relatively resistant C57BL/6 (WT) mice. The mutant mice also showed a delay in B cell activation (CD86, CD80), germinal centre formation and generation of polyclonally-activated B cells (PCB). Interestingly, drug treatment of C57BL/6 with a p110δ specific inhibitor Idelalisib, to generate partial inhibition of the PI3Kδ resulted similarly in improved control of parasitemia in early disease consistent with genetically-deficient p110δD910A mice. Idelalisib treatment also delayed B cell activation of CD80/86 and reduced PCB yet resulted in normal germinal centres. Analysis of cytokine levels in the blood and peritoneal cavity showed a significantly higher proinflammatory (IFN) and lower anti-inflammatory (IL10) environment in the treated group was correlated with lower parasite load in the mice. Further analysis showed that the pattern for lower IL10 production was from specific B cells subsets with regulatory functions (B1) cells in the peritoneal cavity in the treated group compared to the WT. Similarly, we observed increased nitric oxide production which correlated with increased parasite killing in early infection in the treated group. Despite the improved early parasite control, there was a 100% mortality in the genetic mutants (p110δD910A) and 25% mortality in the Idelalisib treated group presumably due to compromised generation of parasite-specific antibodies. In conclusion, our findings suggest that PI3Kδ has both regulatory functions affecting the initial innate immune response necessary for the early control of trypanosomiasis and subsequently critical functions in generating protective antibodies necessary for long term parasite control and survival. These findings may provide insights into potential pathways that could be targeted to modulate immunity to trypanosome infections and may impact the ongoing search for an effective therapy for the disease.