Mucosal Associated Invariant T (MAIT) cells are a population of innate effector T cells which respond rapidly after challenge, producing a milieu of cytokines and lytic molecules which drive host-protective responses to a range of bacterial and viral infections. These rapid and robust responses require significant energy to support cellular biogenesis. Our research is focused on mapping the metabolic responses of human MAIT cell responses. Previous work from our group highlighted the importance of a MYC controlled glycolytic metabolic programme after TCR engagement. We have built on this work by highlighting key nutrients for TCR responses such as glutamine, which is essential for MAIT cell responses including MYC activity. In addition to TCR-driven activation, MAIT cells can also be triggered by the recognition of innate cytokines. However, the metabolic regulation of MAIT cell innate cytokine driven responses remain unclear. To this end, we performed high-resolution, quantitative proteomic analysis and observed significant remodelling of the MAIT cell proteome, with robust increases in protein biosynthesis after innate cytokine stimulation. This remodelling is accompanied by an early glycolytic burst, supporting early IFNg and granzyme B responses, followed by robust production of ISG15, all of which are dependent on the breakdown of glycogen, and glucose. Finally, we elucidate an intrinsic role for ISG15 in driving MAIT cell responses to innate cytokine stimulation, using a CRISPR-Cas9 knockdown approach in primary human MAIT cells, we demonstrate impaired metabolic rewiring, cellular biosynthesis, and MAIT cell effector function in response to innate cytokine stimulation. Collectively, our work defines a novel role for ISG15 in driving the metabolic and functional kinetics of MAIT cell responses to innate cytokine stimulation.