The compositional analysis of heavy petroleum nickel porphyrins by electrospray ionization (ESI) is challenged by their trace amount and relatively low response. In the presented study, we developed a method to enhance the response of nickel porphyrins in ESI by introducing the electrochemical oxidation reaction. The effect of ESI type, solvent, and additives were investigated for standard compounds and heavy oils. The results showed that the ESI source with high positive needle voltage is suitable for nickel porphyrins analysis using dichloromethane as the solvent and trifluoroacetic acid as the ionization promoter. Under the optimized conditions, nickel and vanadyl porphyrins can be directly ionized as molecular radical cations ([M]+•) via electrochemical oxidation due to their low oxidation potential and gas-phase ionization energy. The method is capable of direct analysis of both nickel and vanadyl porphyrins in a vacuum residue without any prior preparation. We also observed the molecular radical cations of other compounds with high aromaticity and short side chains (such as hydrocarbons, nitrogen- and sulfur-containing species), which indicate that the electrochemical oxidation reaction can be used for nonpolar compounds ESI analysis.