Characteristics of an individual alone cannot exhaustively explain all the causes of poor health, and neighborhood of residence have been suggested to be one of the factors that contribute to health. However, knowledge about aspects of the neighborhood that are most important to health is limited. The main objective of this study was to explore associations between certain features of neighborhood environment and self-rated health and depressive symptoms in Maastricht (The Netherlands). A large amount of routinely collected neighborhood data were aggregated by means of factor analysis to 18 characteristics of neighborhood social and physical environment. Associations between these characteristics and self-rated health and presence of depressive symptoms were further explored in multilevel logistic regression models adjusted for individual demographic and socio-economic factors. The study sample consisted of 9,879 residents (mean age 55 years, 48 % male). Residents of unsafe communities were less likely to report good health (OR 0.88 95 % CI 0.80-0.97) and depressive symptoms (OR 0.81 95 % CI 0.69-0.97), and less cohesive environment was related to worse self-rated health (OR 0.81 95 % CI 0.72-0.92). Residents of neighborhoods with more car traffic nuisance and more disturbance from railway noise reported worse mental health (OR 0.79 95 % CI 0.68-0.92 and 0.85 95 % CI 0.73-0.99, respectively). We did not observe any association between health and quality of parking and shopping facilities, facilities for public or private transport, neighborhood aesthetics, green space, industrial nuisance, sewerage, neighbor nuisance or satisfaction with police performance. Our findings can be used to support development of integrated health policies targeting broader determinants of health. Improving safety, social cohesion and decreasing traffic nuisance in disadvantaged neighborhoods might be a promising way to improve the health of residents and reduce health inequalities.