Vaginal drug delivery offers a critical route for local treatments but is limited by short formulation residence times. This study describes a thermosensitive in situ gel prepared by the cold-dissolution method from a ternary blend of Pluronic F127, Carbopol 940, and HPMC for localized vaginal therapy. We used ibuprofen as a model drug selected for its reported anti-inflammatory and antiproliferative activity. The hydrogels exhibited a constant gelation temperature of 28 °C and high viscosity under simulated physiological conditions; ibuprofen incorporation further reduced susceptibility to gravitational leakage. FTIR, XRD, and DSC analyses confirmed stable physical cross-linking of the polymer network and amorphous molecular dispersion of ibuprofen. Peppas–Sahlin modelling revealed a controlled, sustained release profile (>50% over 24 h) predominantly governed by Fickian diffusion (69%). The blank hydrogel exhibited high biocompatibility (>75% viability). In contrast, the ibuprofen-loaded matrix exhibited a concentration-dependent cytotoxic effect on HeLa cervical cancer cells, reducing cell viability to ~12% at the full extract concentration. Overall, this ternary hydrogel platform represents a stable, promising vehicle for sustained local administration of ibuprofen in the vaginal microenvironment.