The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that establish following exposure to malaria parasites. We identified stimulator of interferon genes (STING) as a critical mediator of type I interferon (IFN) production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted the development of IL-10 and IFNγ co-producing CD4+ T (type I regulatory; Tr1) cells at the expense of other CD4+ T cell subsets. In volunteers participating in controlled human malaria infection studies with P. falciparum, CD4+ T cell sensitivity to STING phosphorylation increased following anti-parasitic drug treatment, and this change was most profound in Tr1 cells. This innate signalling pathway active in CD4+ T cells could be modulated by the small molecule JAK1/2 inhibitor ruxolitinib when administered with artemether/lumifantrine (AL) in experimental malaria, resulting in increased parasite-specific Th1 and diminished Tr1 cell responses. These findings have led to a Phase Ib controlled human malaria infection study with P. falciparum to test whether the use of ruxolitinib with AL is safe and can boost anti-parasitic immunity by transiently inhibiting Tr1 cell development and/or functions (ACTRN 12621000866808). These finding have potential applications in strategies designed to improve vaccine efficacy and/or improve anti-parasitic responses following drug treatment, thereby addressing a major bottleneck in efforts to eliminate malaria.