Ti-6242 is a near alpha titanium alloy, which has excellent high-temperature creep resistance and is widely used in jet engine compressors. This alloy is susceptible to creep fatigue failure under dwell loading below 473 K. The existence of microtextured regions (MTRs) contributes significantly to this fast crack propagation. Mechanical processing in the alpha + beta region has been employed to eliminate MTRs, but the efficiency depends significantly on the applied strain path. Previous investigations based on crystal plasticity finite element (CPFE) simulations have demonstrated the relationship between breakdown efficiency and loading direction. Therein, MTRs with regular geometry and pure initial orientation were used to isolate the effect of loading direction from initial microstructure. In this paper, the behavior of MTRs with realistic initial microstructure was investigated using a hierarchical multiscale modeling framework, and the microscale results were analyzed in detail to understand the behavior of MTRs under different loading conditions. It was shown that a hierarchical multiscale model with realistic initial microstructure at the microscale can reflect the influences from different strain paths, initial orientation distributions, and positions of the region simultaneously. The combined effect of initial orientation distribution and loading direction on the MTR breakdown efficiency is discussed in detail.