The objective of this study was to develop sustained release (SR) matrix tablets of metoprolol succinate (MS), by using different polymer combinations and fillers, to optimize by response surface methodology and to evaluate biopharmaceutical parameters of the optimized product. Matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC); and lactose and dibasic calcium phosphate dihydrate (DCP) as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was subjected to further study like scanning electron microscopy, swelling study and in vivo study in rabbit model. Both in vitro and in vivo study revealed that combining of HPMC K100M (21.95%) with EC (8.85%), and use of DCP as filler sustained the action up to 12 h. The in vivo study of new SR tablets showed significant improvement in the oral bioavailability of MS in rabbits after a single oral dose of 25 mg. The delayed T(max) and lower C(max) indicated a slow and SR of MS from the optimized matrix tablets in comparison with the immediate release dosage form. The developed SR (MS) tablet of improved efficacy can perform therapeutically better than conventional tablet.