The aim of this work was to investigate in-depth interactions of econazole nitrate (ECN), a very poorly water-soluble antifungal agent, with different β-cyclodextrin (βCD) derivatives, and to evaluate the potential synergistic effect of suitable third compounds (l-amino acids, citric acid, hydrophilic polymers). Phase-solubility studies showed the formation of equimolar complexes with all tested CDs, and indicated sulfobutyl-βCD (SBEβCD) as the best complexing and solubilizing agent for ECN, followed by hydroxypropyl-βCD (HPβCD). 1D and 2D (1)H NMR studies demonstrated the actual formation of inclusion complexes of 1:1mol:mol stoichiometry, and gave insight about different inclusion modes of ECN molecule into the CD cavity, simultaneously existing in solution. Among the different tested ternary systems, only those with citric acid (CA) enabled a significant increase in complexing and solubilizing ability towards the drug with respect to the binary ones, indicating a synergistic effect between SBEβCD and CA and the formation of highly soluble ternary complexes, which was further supported by NMR studies. Solid equimolar binary and ternary systems of ECN, CDs and CA were prepared by co-grinding in high energy vibrational micro-mills and characterized by differential scanning calorimetry, X-ray powder diffractometry and in vitro dissolution studies. In the case of binary systems, total sample amorphization, indicative of strong solid state interactions and possible inclusion complex formation, was obtained only for co-ground products with HPβCD and SBEβCD, but they both presented a dissolution profile typical of a supersaturated system, with a limited improvement of drug dissolution efficiency (8.3 and 22.13 times, respectively). On the contrary, the ternary ECN/SBEβCD/CA co-ground product presented superior dissolution properties, increasing the ECN dissolution efficiency of 66.62 times, clearly having the best potential for further development of a novel ECN delivery system for efficient delivery of the drug to the oral cavity, thus improving the therapy of oral candidosis.