The purpose of this study was to enhance the understanding of the health-promoting potential of trees in an urbanized region of the United States. This was done using high-resolution LiDAR and imagery data to quantify tree cover within 250 m of the residence of 7910 adult participants in the California Health Interview Survey, then testing for main and mediating associations between tree cover and multiple health measures. The results indicated that more neighborhood tree cover, independent from green space access, was related to better overall health, primarily mediated by lower overweight/obesity and better social cohesion, and to a lesser extent by less type 2 diabetes, high blood pressure, and asthma. These findings suggest an important role for trees and nature in improving holistic population health in urban areas.