This paper presents a thermo-mechanical fatigue (TMF) life prediction method for titanium alloy TA15 under multiaxial random amplitude loading. Through strain-controlled TMF tests, it was found that under full-reversed cyclic loading, there was a significant presence of mean stress in the stress response. The induced mean stress led to the anomalous phenomenon where the fatigue life of thermal phase angle out-of-phase (TOP) was shorter than that of thermal phase angle in-phase (TIP). Therefore, a new damage calculation model was proposed, which can take into account the pure fatigue damage considering mean stress conversion and the cumulative environmental damage. Uniaxial TMF tests, constant amplitude multiaxial TMF tests, and random amplitude multiaxial TMF tests are conducted to verify the proposed method. The predicted results for all types of tests are in a good agreement with the experimental data.