Liquid crystalline-molecularly imprinted polymer (LC-MIP) particles were first found to possess the floating behavior on the aqueous medium. Combined with molecular recognition, the LC-MIP was fabricated as a novel class of the controlled-release gastric retentive DDS. The LC-MIP was made using co-polymerization of methacrylic acid, 4-methyl phenyl dicyclohexyl ethylene (LC monomer with vinyl group), and ethylene glycol dimethacrylate with S-amlodipine (S-AML) as model template drug. The optimum condition of the preparation of LC-MIP has been obtained relying on release behaviors of S-AML from the LC-MIP. The surface morphology of LC-MIP and three corresponding control samples, i.e., template-free LC-NIP, LC-free MIP, and LC-free NIP, were studied. Applying the LF model for the binding isotherm, imprinting factors was 2.80 for the LC-MIP with the crosslinking degree of 20.0%, whereas 6.70 for the LC-free MIP with high levels of crosslinker (80.0%). Furthermore, the phase transition behaviors of LC-based particles as well as drug-loaded LC elastomers were measured by a differential scanning calorimeter and the formed hydrogen bonding between S-AML and LC-MIP was demonstrated by FT-IR spectra. In vivo imaging experiment proved that the floating LC-MIP had significantly longer gastric residence time (>60 min) than the non-floating MIP reference (<30 min). In vivo pharmacokinetic study showed a plateau region between 1.5 and 22 h on the plasma concentration from the LC-MIP. In spite of lower imprinting factor, the relative bioavailability of the gastro-floating LC-MIP was 180.5%, whereas only 111.7% of the LC-free MIP. As a conclusion, the LC-MIPs indicated potentials for oral administration due to the innovative combination of floating and controlled release properties.