Thermomechanical fatigue tests are performed on SA387Gr11CL2 (1.25Cr-0.5Mo) low alloy steel, which is widely used in the manufacture of coke drum. Thermomechanical fatigue mechanical behavior and life are investigated under different mechanical strain amplitudes. A prediction model of thermomechanical fatigue life is developed according to mechanical strain range, and thermomechanical fatigue life of coke drum with SA387Gr11CL2 low alloy steel in service is estimated based on the proposed prediction model and numerical analysis method. Thermomechanical fatigue life of coke drum with SA387Gr11CL2 low alloy steel in service are discussed under different operating parameters. The results indicate that the mechanical strain amplitude has effect on cyclic response of maximum tensile stress, but it has a limited effect on cyclic response of maximum compressive stress. Thermomechanical fatigue life of SA387Gr11CL2 low alloy steel decreases significantly with the increase of mechanical strain amplitude. The stress–strain hysteresis loops are obviously asymmetric. The thermomechanical fatigue prediction life of this studied coke drum with SA387Gr11CL2 low alloy steel is more than 20 years. Considering the safety of coke drum during operation, the time of vapor heating and steam quenching should be prolonged, and the velocity of oil filling and water quenching should be reduced.