Lymphocyte depletion and immunosuppression are typical clinical characteristics of pigs infected with classical swine fever virus (CSFV). The apoptosis of virus-infected and bystander cells plays a role in the immunopathology of classical swine fever (CSF). Here, we offer the first evidence that autophagy is involved in apoptosis and death of T lymphocytes in the spleen of pigs infected with CSFV. Using immunohistochemical assays, we observed that more LC3II-positive cells appear in the T-cell zone of spleens. Spleen cell apoptosis was demonstrated using flow cytometry and TUNEL staining. Confocal immunofluorescence revealed that partial LC3II-positive cells were simultaneously TUNEL-positive. By cultivating spleen cells ex vivo, we demonstrated that the inhibition of autophagy by 3-MA treatment inhibited apoptosis and death of T lymphocytes caused by CSFV infection but did not have this effect on B lymphocytes. Further observations demonstrated that uninfected cells in the spleen were also undergoing autophagy in vivo. In summary, these results linked autophagy with the apoptosis and cell death of splenic T cells, providing a new outlook to understand the mechanism of T lymphocyte depletion and immunosuppression during CSF.