X-ray diffraction is commonly used in the pharmaceutical industry to determine the atomic and molecular structure of crystals. However, it is costly, sometimes time-consuming, and it requires a considerable degree of expertise. Vibrational circular dichroism (VCD) spectroscopy overcomes these drawbacks while also being highly sensitive to small changes in conformation and molecular packing in the solid phase. Here, we investigate the ability of VCD to distinguish between different crystal forms of the same molecule (polymorphs) and, thereby, identify those with the greatest pharmaceutical potential. First, we developed a universal experimental approach for obtaining reliable and reproducible solid-phase VCD spectra. Using three amino acids (serine, alanine, tyrosine) and one hydroxy acid (tartaric acid) as model pharmaceutical ingredients we investigated an effect of various experimental conditions on resulting VCD spectra. Solid samples were prepared using two techniques: (i) suspension of each model compound in oil (mulling agent); (ii) mixture of the model compound and crystalline powder (matrix) compressed into a pellet. Additionally, to achieve artifact-free results with a maximal signal-to-noise ratio, the following experimental conditions were optimized: time of spectral acquisition (0.5‒3h), mulling agent (Nujol, fluorolube), pellet size (0.7 and 20 mm in diameter) and pellet matrix (KBr, KCl, CsI). Then, the optimized approach was successfully applied to distinguish three polymorphs of the antiviral drug sofosbuvir. Our results suggest that solid-state VCD represents a relatively rapid, cost-effective, and easy-to-use structural probe for the identification of crystal structures, with potential use in pharmaceutics.