Abstract: The RNA‐binding protein polypyrimidine tract binding protein 1 (PTBP1) has been found to have roles in CD4 T‐cell activation, but its function in CD8 T cells remains untested. We show it is dispensable for the development of naïve mouse CD8 T cells, but is necessary for the optimal expansion and production of effector molecules by antigen‐specific CD8 T cells in vivo. PTBP1 has an essential role in regulating the early events following activation of the naïve CD8 T cell leading to IL‐2 and TNF production. It is also required to protect activated CD8 T cells from apoptosis. PTBP1 controls alternative splicing of over 400 genes in naïve CD8 T cells in addition to regulating the abundance of ∼200 mRNAs. PTBP1 is required for the nuclear accumulation of c‐Fos, NFATc2, and NFATc3, but not NFATc1. This selective effect on NFAT proteins correlates with PTBP1‐promoted expression of the shorter Aβ1 isoform and exon 13 skipped Aβ2 isoform of the catalytic A‐subunit of calcineurin phosphatase. These findings reveal a crucial role for PTBP1 in regulating CD8 T‐cell activation.