Significant improvement of the catalytic activity of palladium-based catalysts toward carbon monoxide (CO) oxidation reaction has been achieved through alloying and using different support materials. This work demonstrates the promoting effects of the nanointerface and the morphological features of the support on the CO oxidation reaction using a Pd-Cu/TiO2 catalyst. Pd-Cu catalysts supported on TiO2 were synthesized with wet chemical approaches and their catalytic activities for CO oxidation reaction were evaluated. The physicochemical properties of the prepared catalysts were studied using standard characterization tools including SEM, EDX, XRD, XPS, and Raman. The effects of the nanointerface between Pd and Cu and the morphology of the TiO2 support were investigated using three different-shaped TiO2 nanoparticles, namely spheres, nanotubes, and nanowires. The Pd catalysts that are modified through nanointerfacing with Cu and supported on TiO2 nanowires demonstrated the highest CO oxidation rates, reaching 100% CO conversion at temperature regime down to near-ambient temperatures of ~45 °C, compared to 70 °C and 150 °C in the case of pure Pd and pure Cu counterpart catalysts on the same support, respectively. The optimized Pd-Cu/TiO2 nanowires nanostructured system could serve as efficient and durable catalyst for CO oxidation at near-ambient temperature.