Red mudstone subgrades under wetting-drying cycles frequently suffer from settlement and pavement cracking because of the localized disintegration and softening of fill materials. This study employs enzyme-induced calcium carbonate precipitation (EICP) to modify red mudstone fill material from Gansu Province. Unconfined compressive strength (UCS) tests and crack evolution analysis were conducted on untreated and EICP-treated specimens subjected to wetting-drying cycles. The pore structure of the specimens under wetting-drying cycles was characterized via nuclear magnetic resonance testing, and the curing mechanism was investigated using scanning electron microscopy. Results indicate that the UCS of the specimens is negatively correlated with the cycle number. The EICP-treated specimens under wetting-drying cycles exhibit lower moisture variation rates and reduced dehydration rates than the untreated specimens. Crack ratio and length decrease significantly in the modified specimens. Therefore, EICP can effectively suppress the growth of medium and macropores after wetting-drying cycles. The medium and macropores show an exponential relationship with UCS. This investigation on the mechanical behavior and crack evolution of modified red mudstone fill material under wetting-drying cycles offers critical references for its engineering application in subgrade construction.