In this paper, gelation phenomenon during the crystallization process of cefotaxime sodium (CTX) is systematically studied. First, the gelation process is monitored using a nanoparticle size analyzer; the gel and xerogel are studied by different characterization tools to speculate the gelation mechanism. It is found that the gelation is driven by the crystallization of CTX and the nanoparticles act as gelators before they can be seen by the naked eye. Moreover, the solid-solution interfacial tension used to predict the rate of crystal growth is calculated using the induction periods and solvents are classified using the Hansen solubility parameters method, according to whether it can be gelated by CTX. It is shown that the strong polar interaction between solvent molecules and the carboxyl, amine, or acyl groups exposed on the CTX crystal surface is the key factor for gelation.