Objectives. To determine the effect of heat waves on emergency department (ED) visits for individuals experiencing homelessness and explore vulnerability factors. Methods. We used a unique highly detailed data set on sociodemographics of ED visits in San Diego, California, 2012 to 2019. We applied a time-stratified case-crossover design to study the association between various heat wave definitions and ED visits. We compared associations with a similar population not experiencing homelessness using coarsened exact matching. Results. Of the 24 688 individuals identified as experiencing homelessness who visited an ED, most were younger than 65 years (94%) and of non-Hispanic ethnicity (84%), and 14% indicated the need for a psychiatric consultation. Results indicated a positive association, with the strongest risk of ED visits during daytime (e.g., 99th percentile, 2 days) heat waves (odds ratio = 1.29; 95% confidence interval = 1.02, 1.64). Patients experiencing homelessness who were younger or elderly and who required a psychiatric consultation were particularly vulnerable to heat waves. Odds of ED visits were higher for individuals experiencing homelessness after matching to nonhomeless individuals based on age, gender, and race/ethnicity. Conclusions. It is important to prioritize individuals experiencing homelessness in heat action plans and consider vulnerability factors to reduce their burden. (Am J Public Health. 2022;112(1):98-106. https://doi.org/10.2105/AJPH.2021.306557).