As one of the most important main equipment in the power system, the safe and stable operation of transformer plays a vital role in ensuring the reliability of power supply. Because the three-phase parameters of the main transformer are not the same, the parameters of each phase and the three-phase load of the power grid are also different, resulting in a certain degree of asymmetry between the three-phase current and voltage of the transformer during normal operation. There will be negative sequence and zero sequence current components. The degree of asymmetry is generally small for the high-voltage power grid, but it has a large impact on the low-voltage side of the main transformer. In this paper, the parameters of two main transformers in a substation are quite different, but when they need to run in parallel, whether they can run in parallel, what are the conditions of parallel operation, these problems have been studied in theory and simulation. The results show that the two main transformers can be operated in parallel under suitable conditions. The actual operation result of a substation’s main transformer is normal, which further verifies the correctness of theoretical calculation and simulation.