Naïve T lymphocytes display weaker and slower responses than antigen-experienced cells for reasons that are not well understood. Here we show that T-cell receptor (TCR) stimulation induces distinct ERK and p38 phosphorylation patterns in naïve and antigen-experienced human T cells, and that these contribute to the differential responses shown by these cells. Specifically, TCR ligation triggers the activation of the ERK pathway in naïve cells. This phosphorylation of ERK attenuates subsequent calcium influx and accelerates the degradation of the signalsome. In contrast, anti-CD3 stimulation of experienced cells results in the phosphorylation of p38 via an association with Discs large (Dlg). Thus, there are distinct signaling pathways triggered by TCR ligation that impair signaling in naïve cells and facilitate it in antigen-experienced cells.