Hydrochlorothiazide (HCT), C7H8ClN3O4S2, is a diuretic BCS (Biopharmaceutics Classification System) class IV drug which has primary and secondary sulfonamide groups. To modify the aqueous solubility of the drug, co‐crystals with biologically safe co‐formers were screened. Multi‐component molecular crystals of HCT were prepared with nicotinic acid, nicotinamide, succinamide, p‐aminobenzoic acid, resorcinol and pyrogallol using liquid‐assisted grinding. The co‐crystals were characterized by FT‐IR spectroscopy, powder X‐ray diffraction (PXRD) and differential scanning calorimetry. Single crystal structures were obtained for four of them. The N—H...O sulfonamide catemer synthons found in the stable polymorph of pure HCT are replaced in the co‐crystals by drug‐co‐former heterosynthons. Isostructural co‐crystals with nicotinic acid and nicotinamide are devoid of the common sulfonamide dimer/catemer synthons. Solubility and stability experiments were carried out for the co‐crystals in water (neutral pH) under ambient conditions. Among the six binary systems, the co‐crystal with p‐aminobenzoic acid showed a sixfold increase in solubility compared with pure HCT, and stability up to 24 h in an aqueous medium. The co‐crystals with nicotinamide, resorcinol and pyrogallol showed only a 1.5–2‐fold increase in solubility and transformed to HCT within 1 h of the dissolution experiment. An inverse correlation is observed between the melting points of the co‐crystals and their solubilities.