In the Galapagos Islands, the main road in Santa Cruz is one of the elements involved in bird road mortality along with vehicles and the impacted species. This study reports the number of roadkilled birds found on the road from the Itabaca Channel to Puerto Ayora, and the main factors, whether avian or environmental, involved in bird roadkill mortality. We collected individual carcasses in 2004, 2005, 2006, and 2018 with a prevalence of 278, 252, 265, and 294, respectively, across 21 species. The endemic Yellow Warbler Setophaga petechia aureola was the most affected bird. We used a PRIDIT model to rank the top avian and environmental predictors of road mortality. We found that for the sampled years, bird body size (i.e., 8–35 g) and the endemism status (i.e., endemic/native) were the main predictors of roadkill mortality, along with seasonality (i.e., hot season). Weaker predictors related to the bird (i.e., age and sex) and the environment (ecosystem, road slope, vegetation, or precipitation) are also reported as determinants of roadkill mortality. This study on avian mortality aims to inform conservation strategies to reduce the rate of wildlife avian roadkill on Santa Cruz Island and other islands with similar problems.