This study was designed to develop a once-daily controlled-release matrix tablet of aceclofenac 200 mg (AFC-CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC-CR tablets were carried out in simulated intestinal fluid (pH 6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate-release reference tablet Airtal® 100 mg (Daewoong Co., Korea) and the optimized AFC-CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC-CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near-infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na2CO3) was found to enhance the release rate of the AFC-CR bilayered tablets at early stages and increase the microenvironmental pH (pHM). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained-release pattern for the AFC-CR tablet compared to the Airtal® tablet. AFC-CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC-CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pHM of drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled-release matrix tablet with enhanced patient compliance and better pain control.