A356 alloys processed mostly with the low pressure die casting method are always known to contain casting pores and inhomogeneous microstructure. In this study, the effects of microstructure coarsening and casting pores on the tensile and high-cycle fatigue properties of A356-T6 alloy are comprehensively investigated. The deformation behavior and fracture mechanisms are systematically analyzed by combining tensile tests and crystal plasticity finite element method (CP-FEM) simulations with distinctively initial microstructure features (fine microstructure, coarse microstructure, and coarse microstructure with pores). The results show that microstructure coarsening is presented in the notably grown α-Al dendrites, which leads to the connection and thickening of eutectic regions accompanied by the aggregative distribution of eutectic Si particles. With the coarsening microstructure, microcrack is easier to initiate in those thick eutectic regions, due to the higher stress concentration caused by the aggregated eutectic silicon. Particularly, the dominant crack propagation path changes from the trans-dendrite for fine microstructure to along eutectic regions with coarse microstructure. In addition, it confirms that the casting pores have larger detrimental effects on the tensile and fatigue properties than the microstructure coarsening in the aspects of crack initiation. Stress concentration is prone to be induced at the local edge of pore at the initial loading stage, resulting in the micro plastic deformation and lower fatigue properties. With the rapid strain accumulation in later stage, the microcracks can initiate prematurely at the local edge of pore, and thus lead to obvious decrease in tensile elongation. Moreover, a modified fatigue model considering the effects of casting pores and the microstructure difference is proposed to describe the fatigue performance of A356-T6 alloy.