Abstract: The stability of soil slopes in seasonally frozen soil areas is strongly affected by the coupled environmental processes, particularly wetting–drying and freeze–thaw cycles. However, damage evolution and mechanical response of structural loess under the combined effects of these processes remain poorly understood. By conducting triaxial shear tests of consolidated drainage with different numbers of drying-wetting and freeze-thaw cycles, as well as nuclear magnetic resonance and electron microscope scanning tests, the variation of mechanical properties and damage and deterioration mechanisms of structural loess were analyzed from a macro-mesoscopic perspective. The correlation analysis between the pore changes of microscopic particles and strength parameters was carried out. Finally, the strength criterion of structural loess under the coupling of drying-wetting and freeze-thaw cycles was established, and its rationality was verified. The results show that the soft/hardening characteristics of the stress-strain curve are related to the number of cycles and the magnitude of confining pressure. With the increase in cycle numbers and confining pressure, the stress-strain curve gradually transitions from softening to hardening characteristics. Under the cycle conditions, the strength parameter cohesive force is more damaged than the internal friction angle, and its deterioration rate is higher. After 10 cycles, the pore area increased by approximately 40%. The damage of the cementation blocks led to a gradual increase in the pore area. Micro-small pores transformed into large-medium pores, and a new distribution pattern was formed within the soil. The increase in mesoscale pores was consistent with the deterioration of the macroscopic strength parameters. After the drying-wetting and freeze-thaw, during the shear period, the cementing elements inside the soil gradually transform into friction elements. The evolution of the part of the soil providing strength is cementing-cementing block and weak-weak zone, forming a new strength-bearing mechanism. This research provides a theoretical basis for evaluating and mitigating slope instability in seasonally frozen regions.