Cocrystals of ethinyl estradiol (EE) with five coformers, namely, nicotinamide (NA), piperazine (PZ), tetramethylpyrazine (TET), 4,4′-bipyridine (BIP) and imidazole (IZ) were prepared in 1 : 1 stoichiometry ratio, and their crystal structures were characterized via a series of physicochemical methods. The EE molecules were connected with coformers through intermolecular hydrogen bonds to form chain structures. In particular, EE–NA and EE–TET·H2O have special spiral chain structures and unique combinations. The physical stability experiment under high-temperature, high-humidity and high-light intensity conditions proved the stability of EE cocrystals. Moreover, the dissolution performance was explored, and a prominent “spring-parachute” effect was observed for EE–NA in 0.2% SDS solution to improve the EE solubility (1.43-fold), and EE–PZ and EE–TET·H2O also had some advantages over EE. This successful attempt implies that the cocrystallization strategy is an effective means to improve the solubility and stability of EE.
