This study has investigated the potential use of zein protein from corn as a pharmaceutical excipient for formulation of oral controlled-release matrices. SMCC (silicified microcrystalline cellulose)-Prosolv® 90, SMCC HD-Prosolv® 90 HD, Avicel® PH 102 and Mannitol 60 were evaluated as co-excipients to improve the processability of zein powder. Zein/SMCC-Prosolv® 90 blend had the best flowability and tabletability. Tablets with tramadol hydrochloride, zein and SMCCProsolv® 90 were prepared by direct compression. Drug release from the tablets was measured by dissolution testing. The dissolution profiles obtained were compared using the dissolution efficiency (DE) and were fitted to the Korsmeyer–Peppas equation. Controlled drug release, governed by anomalous (non-Fickian) drug transport, was obtained over the test duration. Drug release rate and mechanism were dependent on formulation parameters, such as tablet hardness, zein/SMCC ratio and drug loading, as well as medium pH. Dynamics of tablets swelling correlated well with drug release rate and mechanism, with faster drug release and greater contribution of polymer relaxation being obtained at increased swelling. In conclusion, the present work has shown that zein/SMCC based matrix formulation can be used as a new platform for oral-controlled drug delivery which can be easily customized by adjusting formulation parameters. The use of this formulation could be attractive for customers and manufacturers who prefer to avoid synthetic or chemically modified excipients.