Ribavirin (C8H12N4O5; anti-viral agent) was crystallized as two unique, phase-pure polymorphs (R-I and R-II). Calorimetrically determined isobaric heat capacities and heat of transition data were utilized to determine the solid-state transition temperature (Ttr), confirming enantiotropism, while R-I was determined to be kinetically stable at ambient temperature. Unprocessed samples of the low Tm polymorph, R-II, did not convert into R-I when held isothermally well above Ttr for 7 days. In contrast milled R-II completely transformed to R-I after 15 min at the same storage conditions, indicating that defects sustained during processing reduced the energy barrier for transformation, allowing it to occur. R-II was subjected to both cryogenic milling and impact milling at ambient temperature for various durations. Cryomilling resulted in an in situ progressive reduction of crystallinity, with complete conversion to amorphous ribavirin after 2 h. Limited molecular mobility attributable to the low milling temperature (Texp = −196 °C) likely inhibited recrystallization, allowing the amorphous solid to persist. In contrast, continuous impact milling at ambient temperature resulted in complete in situ conversion from R-II to R-I after 3 h. The data suggested rapid conversion to R-I from highly disordered regions during extended milling, facilitated by localized heat buildup that likely exceeded Tg and/or Ttr.