Cold in-place recycling (CIR) asphalt mixtures are an attractive eco-friendly method for rehabilitating asphalt pavement. However, the on-site CIR asphalt mixture generally has a high air void because of the moisture content during construction, and the moisture susceptibility is vital for estimating the road service life. Therefore, the main purpose of this research is to characterize the effect of moisture on the high-temperature and low-temperature performance of a CIR asphalt mixture to predict CIR pavement distress based on a mechanistic–empirical (M-E) pavement de-sign. Moisture conditioning was simulated by the moisture-induced stress tester (MIST). The moisture susceptibility performance of the CIR asphalt mixture (pre-mist and post-mist) was estimated by a dynamic modulus test and a disk-shaped compact tension (DCT) test. In addition, the standard solvent extraction test was used to obtain the reclaimed asphalt pavement (RAP) and CIR asphalt. Asphalt binder performance, including higher temperature and medium temperature performance, was evaluated by dynamic shear rheometer (DSR) equipment and low-temperature properties were estimated by the asphalt binder cracking device (ABCD). Then the predicted pavement distresses were estimated based on the pavement M-E design method. The experimental results revealed that (1) DCT and dynamic modulus tests are sensitive to moisture conditioning. The dynamic modulus decreased by 13% to 43% at various temperatures and frequencies, and the low-temperature cracking energy decreased by 20%. (2) RAP asphalt incorporated with asphalt emulsion decreased the high-temperature rutting resistance but improved the low-temperature anti-cracking and the fatigue life. The M-E design results showed that the RAP incorporated with asphalt emulsion reduced the international roughness index (IRI) and AC bottom-up fatigue pre-dictions, while increasing the total rutting and AC rutting predictions. The moisture damage in the CIR pavement layer also did not significantly affect the predicted distress with low traffic volume. In summary, the implementation of CIR technology in the project improved low-temperature cracking and fatigue performance in the asphalt pavement. Meanwhile, the moisture damage of the CIR asphalt mixture accelerated high-temperature rutting and low-temperature cracking, but it may be acceptable when used for low-volume roads