In this study, a laboratory experimental program was conducted to investigate the effect of asphalt content and air voids on the material properties and fatigue performance characteristics of asphalt concrete mixtures. Two levels of asphalt content (4.2 and 5.2%) and air voids (4.5 and 9.5%) were considered to produce four asphalt concrete mixture combinations. The advanced material characterization tests included dynamic (complex) modulus for stiffness evaluation and the uniaxial tension-compression for fatigue assessment. The fatigue analysis was performed for each mixture using the simplified viscoelastic continuum damage (S-VECD) approach. The damage characteristic (C-S) curves were established for each of the four mixtures. To have more useful information about the fatigue resistance of the four mixtures, the C-S curves were used to obtain the fatigue relationships by performing simulated predictions of the fatigue life at specific conditions. It is found that the S-VECD simulations are able to reflect the observed material trends. Simulations performed with this model also suggest that the impact of air void and asphalt content changes differ between stress-controlled and strain-controlled loading. The quantification of these differences may have implications in both pavement and material analysis and design.