The spherulitic morphology is considered to be the most common morphology of crystalline materials and is particularly apparent in melt-crystallized products. Yet, historically, the polycrystalline nature of spherulites has hindered successful crystal structure determination. Here, we report for the first time the direct structure determination of a small molecule organic compound in spherulite form using 3D electron diffraction (3D ED). We employed vemurafenib (VMN), a clinical drug used for the treatment of BRAF-mutant melanoma, as a model compound. VMN has four known polymorphs (α-, β-, γ-, and δ-VMN), three of which were discovered by melt crystallization. We first solved the crystal structures of α-, β-, and γ-VMN from both open and compact spherulite samples using 3D ED, and the resulting structures were highly consistent with those solved by single-crystal X-ray diffraction. We then determined the previously unknown crystal structure of δ-VMN—the least stable polymorph which cannot be cultivated as a single crystal—directly from the spherulite sample resulting from spontaneous nucleation. We unexpectedly discovered a new polymorph during our studies, denoted as Form ε. Single crystals of ε-VMN are extremely thin and are not suitable for study by X-ray diffraction. Again, we determined the structure of ε-VMN from both open and compact spherulite forms. This successful structure elucidation of all five VMN polymorphs demonstrates the possibility of removing the time-consuming step of single crystal growth and directly determining structures from spherulite samples. Thereby, this discovery will improve the efficiency and broaden the scope of polymorphism research, especially within the field of melt-crystallization.