Development of a sustained release liquid oral in-situ gel of Voriconazole with improved bioavailability has been the main aim of this project. Complexation of the drug with hydroxypropyl betacyclodextrin was done to improve the solubility and stability of the drug. The mucoadhesive polymer carbopol 934P and release retardant HPMC E50 were used as factors, and a two-square factorial design was employed. A simple mixing method was used for the formulation, and evaluation was done. The polymers had a significant effect on gelation time, mucoadhesive strength, and 8 h drug release. Carbopol showed a better-controlled release and mucoadhesive strength than HPMC E50. The experimental values for gelation time, mucoadhesive strength, drug release at 1 h, 8 h, 12 h, and gel strength were found to be 80 sec, 17453 dynes/cm, 21.10%, 62.98%, 90.54%, 55 sec respectively, which were close to the predicted values. Pharmacokinetic studies revealed a 12 h sustained drug release, plasma drug concentrations above 0.5µg/ml (MIC) and 6.76-fold increase in bioavailability. Thermal and photostability studies revealed a shelf life of 2 years. Equivalence testing proved that the prepared formulation was better than the reference as the ϴtest (0.6835) < ϴstd (0.7963). An elegant, needle-free liquid oral in-situ gel of Voriconazole could thus be successfully developed by statistical optimization techniques using mucoadhesive polymers to sustain the drug release up to 12 h, improve bioavailability and patient compliance.