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Abstract Lipid‐coated microbubbles are an important class of gene delivery vehicles activated by ultrasound to locally deliver their DNA payloads to cells. Negatively charged DNA is electrostatically loaded onto the positively charged surface of microbubbles that contain a cationic lipid shell. Characterizing the zeta potential of individual cationic microbubbles to determine a population distribution and how this is affected by DNA complexation is critical to maximize DNA loading and circulation time. Traditional zeta potential analysis provides an ensemble charge measurement for a particle population but cannot measure individual particles to determine a distribution. Here, single‐particle tracking microelectrophoresis technology is applied to measure zeta potentials of individual microbubbles synthesized with different ratios of 1,2‐distearoyl‐3‐trimethylammonium‐propane (DSTAP) cationic lipid as well as loaded with increasing amounts of DNA. Results show that at 0 mol% DSTAP all microbubbles are negatively charged, and at 10 mol% half are positive. All particles are positive at 20 mol% DSTAP but the population shifts to negative values upon incubation with 0.01 pg DNA/microbubble. Analyzing zeta potential on the individual microbubble level is a powerful tool to understand DNA loading across a population of microbubbles and enables microbubble surface charge and nucleic acid loading optimization for delivery applications.