Built on the recent successes in understanding the crystallographic mechanism for short fatigue crack (SFC) growth across a grain boundary (GB) and developing an experimental method to quantify the GB resistance against short crack growth, a microstructure-based model was developed in this study to simulate the growth behaviors of SFCs in 3-D, by taking into account both the driving force and resistance along at each point along the crack front in an alloy. It was found that the GB resistance was a Weibull function of the minimum twist angle of crack deflection at the boundary in AA2024-T3 Al alloys. In the digital microstructure used in the model, the resistance at each GB that the short crack interacted with could be calculated, as long as the orientations of grains and the crack were known. In the model, an influence function accounting for the overlapping effect of the resistance from the neighboring grain boundaries was proposed, allowing for calculation of the total resistance distribution along the crack front. In order to overcome the time consuming problem for the existing equations to derive the distribution of stress intensity factor along the crack front under cyclic loading, an analytical equation was proposed to quantify the stress intensity factor distribution along an irregular shape planar crack. By introducing two shape-dependent factors, the fractured area and the perimeter of the crack front, the newly proposed equation could readily and accurately derive the stress intensity factor distribution along the crack front that had large curvatures and singularities. Finally, a microscopic-scale Paris’ equation was proposed that took into account both the driving force, i.e., stress intensity factor range, and the total resistance to calculate the growth rate at each point along crack front. The model developed in this work was able to incorporate microstructure, such as grain size and shape, and texture into simulation of SFC growth in 3-D. It was capable of simulating all the anomalous growth behaviors of SFCs, such as the marked scatters in growth rate measurement, retardation and arrest at grain boundaries, and crack plane deflection at grain boundaries, etc. The model was used to simulate the growth behaviors of SFCs initiated from prefractured constituent particles in order to interpret the multi-site fatigue crack initiation observed in AA2024-T351 Al alloys. Three types of SFCs were observed initiating from these particles, namely, type-I non-propagating cracks; type-II cracks which were arrested soon after propagating into the matrix; and type-III propagating cracks. To quantitatively study the 3-D effects of particle geometry and micro-texture on the growth behaviors of micro-cracks in these particles, rectangular micro-notches with different dimensions were fabricated using focused ion beam in the selected grains on the T-S planes in AA2024-T351 Al alloys, to mimic the pre-fractured particles in these alloys. Knowing the notch dimensions or particle shape, grain orientation and GB geometry, the simulated crack growth behaviors were consistent with the experimental observations, and the model was able to verify that the three types of cracks evolved from these particles were mainly associated with the thickness and width of the pre-fractured particles, though the particle geometry and grain orientation could also affect the behaviors of fatigue crack initiation at the particles. When the widths of the particles were less than 15 μm, like in most high strength Al alloys, the simulated results confirmed that the crack type was only associated with the particle thickness, consistent with the experimental results in AA2024-T351 alloys with a strong rolling texture. The lives for the SFCs to reach 0.5 mm in length were quantified with the model in the AA2024 alloy, revealing that there was a bimodal distribution in the life spectrum calculated, with the longer life peak being related to larger twist angles of crack deflection at the first GB the cracks encountered and the shorter life peak being associated with small twist angles (< 5°) at the first GB. The model further demonstrated the influence of grain structure on SFC growth by considering two different grain structures with the same initial short crack, namely, a layered grain structure with only the primary GBs perpendicular to the surface and the layered grains with both primary and secondary GBs. Depending on their positions and geometry, the secondary GBs could still exert a strong retarding effect on SFC growth on surface. The model was validated by matching to the growth rate measured on surface of a SFC in an AA8090 Al-Li alloy. Good consistency was achieved between the simulated and experimentally measured growth rates when both the primary and secondary GBs were considered in the model. The model developed in this study exhibits its potential applications to optimizing the microstructure and texture in alloys to enhance their fatigue resistance against fatigue crack growth, and to satisfactory life prediction of engineering alloys.