In the presence of water, thermal simulation experiments on the reaction between CH4 and MgSO4 were conducted at high temperatures and high pressures. Chemical and carbon isotopic variations were characterized with advanced analytical methods, including microcoulometry, gas chromatography, Fourier transform infrared spectroscopy, X-ray diffraction, and gas chromatograph combustion isotope ratio mass spectrometry. It was found that CH4 can react with MgSO4 to produce H2S, CO2, and MgO as the main products of thermochemical sulfate reduction. The carbon kinetic isotope fractionation was tentatively investigated using quantum chemistry and the kinetic isotope effect was calculated.