Oral cancer has a high mortality rate, and its treatment often causes debilitating complications. More than 90% of oral cancers are oral squamous cell carcinomas (OSCCs) that may develop from clinically recognizable oral premalignant lesions (OPLs). To eradicate OPLs before they turn into cancers, a non‐invasive topical formulation is developed based on a novel combination of synergistically acting oxaliplatin (OXP) and mycophenolate (MPS) embedded in a controlled‐release mucoadhesive patch fabricated by computer‐aided 3D printing. After multiple rounds of testing and optimization, a v6.4 ChemoPatch is designed, which shows sustained release of OXP and MPS in vitro, minimal side leakage of drugs, an average elastic modulus of 2.38 MPa, and suitable drug stability at 4 °C or below for up to 12 months. In vivo analyses show almost all patches adhere to the dorsal tongue surface for 4 hours, and display a sustained release of OXP and MPS to tongue tissue for 3–4 hours. When applied in the 4‐nitroquinoline‐1‐oxide‐induced OPL rat model, the OXP‐MPS patch significantly ablates dysplastic lesions with no damage to normal epithelial cells and minimal systemic absorption and side effects. This study reports the design of a novel mucoadhesive ChemoPatch as a noninvasive therapy to treat OPLs. A mucoadhesive ChemoPatch is invented to provide a non‐invasive therapeutic option for treating oral premalignant lesions, thereby preventing oral cancer formation. The design is based on synergistically acting drug pairs, delivered by a 3D‐printed multi‐layered mucoadhesive patch formulation in a controlled and sustained manner. Analyses of the ChemoPatch confirm its preclinical potential in treating oral precancer.