Background/Objectives: Amorphous drug products are susceptible to crystallisation during manufacture or storage, which may alter dissolution and pharmacokinetics (PK). Tacrolimus, a low-solubility, high-permeability drug, relies on amorphous formulations to achieve adequate absorption, making crystallisation a key quality risk. Physiologically based pharmacokinetic (PBPK) models with simultaneous tracking of amorphous and crystalline fractions as different solid states within the gut enable a mechanistic assessment of how crystallinity may influence PK and bioequivalence (BE) outcomes. Methods: A PBPK model incorporating mechanistic dissolution was developed to evaluate the impact of tacrolimus solid-state composition on BE. Model performance was verified against clinical PK data for formulations spanning a range of crystallinity levels. Virtual BE (VBE) assessments were conducted using two-way and fully replicated four-period crossover designs. Within-subject variability (WSV) was introduced mechanistically through physiological parameters. Results: The PBPK model adequately reproduced the crystallinity-dependent PK of tacrolimus observed in clinical studies. VBE simulations captured the reported trend of crystallinity-driven bioinequivalence, with increasing crystallinity primarily influencing C_max and having a limited effect on AUC_0–24h, suggesting a predominant impact on absorption rate. Model-based extrapolation beyond the clinically evaluated range indicated that crystallinity levels of 5–15% may be associated with a higher likelihood of meeting BE criteria under a fully replicated four-period crossover design. Conclusions: Mechanistic PBPK modelling enabled extrapolation beyond clinically tested crystallinity levels by linking solid-state behaviour to in vivo performance. This approach can complement experimental evidence and support BE assessment and risk evaluation during formulation development, clinical evaluation, and post-approval change management.