Direct ethanol fuel cells are among the most promising clean electrochemical power sources. Nevertheless, the high cost and low efficiency of the Pt-based catalysts hinder their commercialization. Here, Pt-Sn-Co nanocubes with a Pt- and Sn-rich shell show improved performance towards the electrochemical ethanol oxidation reaction. Mechanistic and structural insights were obtained by synergistically combining different in situ and operando spectro-electrochemical techniques, including electrochemical mass spectrometry, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy. In particular, electrochemical conditioning and EOR were found to induce Sn leaching from the core and shell, leading to electrochemically-accessible Pt sites adjacent to partially-oxidized Sn sites on a Pt3Co-like core. The increased activity of the Pt-Sn-Co nanocubes was assigned to the formation of a higher amount of C1 (CO2) and C2 (acetic acid/acetaldehyde) products during EOR as well as to their high ability to remove adsorbed CO from the Pt surface when compared to similarly-sized cubic Pt-Sn or Pt NPs. Beneficial strain and ligand effects are combined here through a catalyst design resulting in adjacent Pt and Sn sites at the overlayer on top of a Pt3Co alloy core.