Candida albicans, as the main causative fungus of vaginal candidiasis, is currently a global issue of concern due to its high prevalence, biofilm formation and emergence of resistance. Ketoconazole (KTZ), an antifungal drug, which has poor water-solubility and penetration capacity, is ineffective against deep-seated Candida infection. Considering these issues, this work aimed to develop a novel multifunctional carrier for KTZ via encapsulation of KTZ/β-cyclodextrin (β-CD) co-ground mixture into chitosan/gellan gum gel-flakes (threadlike and polygonal structures). Analytical studies revealed existence of electrostatic-derived complexes between negatively charged gellan gum and positively charged chitosan. Gel-flakes were then loaded in in situ gel of pluronic F-127 (PF-127). Based on gelation temperature (Tgel), viscosity and release studies; selected formulation was further evaluated, showing significant in vitro anti-candida activity. Despite reduced dosage regimen (50 mg/daily/three days), KTZ flakes in situ gel was as effective as Gynoconazol vaginal cream® (80 mg terconazole/daily/three days) in im- proving patient complaints and Candida eradication. Multifunctionality of KTZ carrier was based on efficient spreading and coating of the vagina due to free-flowing properties during application, flakes entanglement within folded vaginal epithelia, sustained release and increased penetration capacity of KTZ to reach deep-seated infections. In conclusion, flakes in situ gel could be considered as a highly promising KTZ delivery option for treatment of vaginal candidiasis.