The aim of this study was to develop and evaluate an extended-release (ER) push-pull osmotic pump (PPOP) tablet for phencynonate HCl (PCN), which could release the drug at zero-order profile for a duration of 24 h. The core tablets were designed as bi-layered, primarily composed of sodium chloride and polyethylene oxide (PEO). The central composite design (CCD) within a response surface methodology (RSM) was used to optimize the formulation. An optimized PCN-PPOP tablet formulation was achieved with the following values for key factors: 10 mg NaCl, 70 mg PEO, and 13.56% coating membrane weight gain. It revealed that this formulation could release PCN in vitro at a zero-order manner for 18 h. The in vivo release property of the PCN-PPOP tablet was assessed and contrasted with that of immediate-release (IR) tablet following a single oral administration to beagle dogs. The pharmacokinetic data indicated that the PPOP tablet achieved a sustained in vivo release of PCN, as evidenced by a longer Tmax (7.17 ± 1.83 h) and mean residence time (11.57 ± 1.12 h). This work demonstrated that PCN-PPOP tablet could be designed for oral administration to provide a long-term pharmacological intervention for motion sickness.