In recent years, several studies have shown that Rhodiola rosea can enhance cellular immunity and humoral immune function in mice, and thus, it has become a research hotspot. However, its underlying mechanism of action has remained elusive. The present study investigated whether Rhodiola rosea was able to downregulate the expression of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2), thereby inhibiting the expression of apoptotic genes, attenuating T-lymphocyte apoptosis and improving immunity in septic mice. A mouse model of caecal ligation and puncture (CLP)-induced sepsis was established, and animals in the treatment group were pre-treated with an intraperitoneal injection of Rhodiola rosea extract, while animals in the control group and sham-operated group were injected with an equivalent amount of normal saline. TIPE2, B-cell lymphoma 2 (Bcl-2), Fas and Fas ligand (FasL) mRNA and protein levels in thymic T cells were determined using reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. Furthermore, the thymus T-lymphocyte apoptosis rate, thymus T-lymphocyte count and thymus T-lymphocyte sub-sets were assessed using flow cytometry. Levels of T-helper cell type 1 (Th1) cytokines [Interleukin (IL)-2, IL-12 and interferon (IFN)-γ] and Th2 cytokines (IL-4 and IL-10) were determined using ELISA. The results showed that, compared to that in the CLP group, the expression of TIPE2, Fas and FasL in the treatment group was significantly decreased, while the expression of Bcl-2 was increased (P<0.05). The thymus lymphocyte count in the CLP group was significantly higher compared with that in the treatment group (P<0.05). Furthermore, the apoptotic rate of thymus T-lymphocytes in the treatment group was significantly lower than that in the CLP group (P<0.05). In addition, treatment with Rhodiola rosea rescued decreased in the counts of the CD3(+) T and CD4(+) T sub-sets of thymus T lymphocytes in the CLP group (P<0.05), while not affecting the increased levels of Th2 cytokines (IL-4 and IL-10) in the CLP group compared with those in the control groups. In addition, the Th1 cytokines (IL-12, IL-2 and IFN-γ) were significantly increased (P<0.05) in the CLP group, and treatment with Rhodiola rosea led to further increases. The thymus index of septic mice treated with Rhodiola rosea as well as their survival rate were improved as compared with those in the CLP group. These findings suggested that Rhodiola rosea has protective effects against sepsis by decreasing apoptosis, increasing Th1 cytokines and enhancing the host's immunity via the regulation of TIPE2 expression.