BACKGROUND: Recent evidence suggests that higher levels of residential greenness may contribute to better mental health. Despite this, few studies have considered its impact on depression, and most are cross-sectional. OBJECTIVE: The objective of this study was to examine surrounding residential greenness and depression risk prospectively in the Nurses Health Study. METHODS: A total of 38,947 women (mean age throughout follow-up 70 y [range 54–91 y]) without depression in 2000 were followed to 2010. Residential greenness was measured using the satellite-based Normalized Difference Vegetation Index (NDVI) and defined as the mean greenness value within [Formula: see text] and [Formula: see text] radii of the womens residences in July of each year. Incidence of depression was defined according to the first self-report of either physician-diagnosed depression or regular antidepressant use. We used Cox proportional hazards models to examine the relationship between greenness and depression incidence and assessed physical activity as a potential effect modifier and mediator. RESULTS: Over 315,548 person-years, 3,612 incident depression cases occurred. In multivariable-adjusted models, living in the highest quintile of residential greenness within [Formula: see text] was associated with a 13% reduction in depression risk ([Formula: see text] [95% confidence interval (CI): 0.78, 0.98]) compared with the lowest quintile. The association between greenness and depression did not appear to be mediated by physical activity, nor was there evidence of effect modification by physical activity. CONCLUSIONS: In this population of mostly white women, we estimated an inverse association between the highest level of surrounding summer greenness and the risk of self-reported depression. https://doi.org/10.1289/EHP1229.