The effect of moisture on the fracture resistance of asphalt concrete is a significant concern in pavement engineering. To investigate the effect of the water vapor concentration on the fracture properties of asphalt concrete, this study first designed a humidity conditioning program at the relative humidity (RH) levels of 2%, 50%, 80%, and 100% for the three types of asphalt concrete mixtures (AC-13C, AC-20C, and AC-25C).The finite element model was developed to simulate the water vapor diffusion and determine the duration of the conditioning period. The semi-circular bending (SCB) test was then performed at varying temperatures of 5 °C, 15 °C, and 25 °C to evaluate the fracture energy and tensile strength of the humidity-conditioned specimens. The test results showed that the increasing temperature and the RH levels resulted in a lower peak load but greater displacement of the mixtures. Both the fracture energy and tensile strength tended to diminish with the rising temperature. It was also found that moisture had a significant effect on the tensile strength and fracture energy of asphalt concrete. Specifically, as the RH level increased from 2% to 100% (i.e., the water vapor concentration rose from 0.35 g/m³ to 17.27 g/m³), the tensile strength of the three types of mixtures was reduced by 34.84% on average, which revealed that the water vapor led to the loss of adhesion and cohesion within the mixture. The genetic expression programming (GEP) model was developed to quantify the effect of water vapor concentrations and temperature on the fracture indices.