Fluorogenic dyes enable highly sensitive, real-time fluorescent readouts in live cells. Recent applications of fluorogenic dyes with self-labeling enzymes has expanded their applications, allowing high spatial and temporal resolution. However, improving fluorogenic self-labeling enzyme systems has largely focused on synthetically modifying the substrate dye and not the self-labeling enzyme. Here, we use molecular evolution to optimize the self-labeling enzyme HaloTag7 for improved performance with a designed fluorogenic substrate. Screening over 250 million variants, we isolated the optimized enzyme BenzoHTag which shows low background and rapid turn-on fluorescence in live mammalian cells.