<p>Most studies on the fatigue performance of cement concrete pavements overlook the different mechanical characteristics between tension and compression and complex service conditions. This limits the accuracy of durability evaluation. To address this issue, this study investigated four-point bending fatigue tests considering tension–compression differences. The decay patterns of tensile and compressive moduli were revealed. A numerical model was developed, incorporating coupled tensile–compressive stress fields and temperature fields in the cement pavement structure. The evolution of structural responses was analyzed. Results showed that the four-point bending fatigue life before and after considering tension–compression differences differ by more than 90%. A correlation between the two conditions was established. The moduli decay rates followed a power-law relationship with stress level. A unified fatigue decay model for tensile and compressive moduli was established. The decay rate of tensile modulus was higher than compressive modulus. At failure, the ratio of compressive to tensile modulus was up to 3.5 times the initial stage. The tensile modulus decay was the key dominant factor in fatigue failure. Mechanical response varied as power functions with axle load cycles. The maximum tensile stress at the base layer bottom increased over 140%. When axle load cycles exceeded two-thirds of total design life, the surface layer lost more than 75% of service life, and the base layer began to decay rapidly. This revealed the evolution mechanism of structural stress: “surface deterioration—base takeover—structural instability”. The findings provide a basis for durability design of cement concrete pavements under complex service conditions.</p>