The present study was conducted to determine the effect of Diplazium esculentum on Th1 and Th2 cytokine modulation in Swiss albino mice that were administered orally with different doses of boiled D. esculentum (BDE), daily within a span of 180 days. After the treatment, serum was collected. Splenocytes were also cultured in vitro with different concentrations of BDE, and culture supernatant was collected. Both serum and culture supernatant were used for cytokine determination by enzyme-linked immunosorbent assay (ELISA) for different Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines. Results indicated significant decreases (p < 0.05, p < 0.01, and p < 0.001) in both Th1 and Th2 cytokine concentrations when compared with their respective controls. These results suggest that the intake of D. esculentum, even after cooking, may evoke immune dysfunction by altering Th1 and Th2 cytokine balance, may induce severe immunosuppression, and may be considered as alarming.