A novel once-monthly sustained-release injectable dosage form of Lurasidone hydrochloride thermosensitive hydrogel (LURA-H-THG) developed using PLGA-PEG-PLGA, for the treatment of schizophrenia. The optimized formulation (LURA-H-THG3), prepared via multi-step mixing technique demonstrated favorable particle size, rapid gelation time (10 s), and a gelation temperature (36.0 ± 2.0 °C). Size exclusion chromatography and drug content analyses confirmed drug–polymer complexation and quantitatively consistent drug loading (101.0 %). Oscillatory rheology demonstrated elastic behavior (storage modulus, G’ > loss modulus G”), exhibiting mechanical integrity. Fourier-transform infrared spectroscopy revealed no chemical interaction, and differential scanning calorimetry confirmed the amorphous state of LURA-H. In vitro release in phosphate buffer saline, pH 7.4, exhibited sustained drug release over 30 days. Stability studies at 25 ± 2 °C and 60 ± 5 % RH showed consistent physicochemical characteristics. A pharmacokinetic study in rats and the antipsychotic activity of LURA-H-THG3 in mice demonstrated sustained pharmacokinetic and in vivo antipsychotic activity, with approximately six-fold improvement in bioavailability and reduced extrapyramidal side effects over oral LURA-H. This study is first to simulate human plasma levels of the LURA-H formulation using in silico GastroPlus™ 9.8 modeling, supporting its translational potential as an innovative drug delivery system with potential to broaden treatment options across multiple therapeutic indications.