Calix[4]arene, a class of host compounds, is capable of forming host-guest compounds with guest molecules through hydrogen bonding, electrostatic forces, or van der Waals forces. With the incorporation of sulfur atoms into the molecular structure of calix[4]arene, the cavity size of calix[4]arene would increase. At the same time, sulfur atoms offer strong coordination abilities to trace amounts of variable metallic ions (Mn²⁺, Cu²⁺) presented in natural rubber. The complexes prepared by sulfothiacalix[4]arene salt and metal ions can mitigate catalytic effects of variable metallic ions on the aging reactions of natural rubber, thus improving the thermal oxidative aging performance of natural rubber. Sulfothiacalix[4]arene was synthesized and the protective effect of sulfothiacalix[4]arene on the thermo-oxidative aging behavior of natural rubber was investigated by means of FTIR, DSC, TGA and so on. After the experiment, compared with the samples without the addition of sulfothiacalix[4]arene, it was found that the signals of O-H, C=O and C=C in the FTIR spectra of the samples with the addition group were weakened, the thermo-oxidative aging temperatures on the DSC curve were increased by about 18.87 ℃ and 29.90 ℃, and the epitaxial initial thermal decomposition temperatures in TGA were increased by 11.82 ℃ and 15.03 ℃, respectively. It is concluded that sulfothiacalix[4]arene could be used as a highly effective anti-aging agent in the thermo-oxidative aging of natural rubber.