Experiences of childhood maltreatment are a substantial risk factor for the development of major depressive disorder in adulthood. Often, those who experience major depressive disorder and childhood maltreatment tend to have an overall worse prognosis, including a greater number of depressive symptoms, higher risk for death by suicide, and higher likelihood to not respond to treatments. Strong theoretical evidence suggests that experiences of childhood maltreatment may increase inflammatory signaling that targets the brain, creating depressive symptoms. This dissertation presents three studies that explore these associations with the goal of identifying novel treatment and prevention strategies for major depressive disorder related to childhood maltreatment. The first study presents a longitudinal, repeated measures model to assessing the association between the early life social environment, inflammation, and depressive symptoms across the first four decades of life using a nationally representative U.S. sample. Results from the first study indicate that reducing socioeconomic inequalities early in life could reduce the risk of childhood maltreatment while also reducing depressive symptoms and C-reactive protein in adulthood. Further, results from the first study indicate that a reduction in depressive symptoms early in life could reduce adipose tissue as measured by body mass index which increases inflammation. The second study presents results from a longitudinal path model exploring the association between individual adverse childhood experiences, C-reactive protein, and depressive symptoms. Results from the second study indicate that the broad category of adverse childhood experiences can have complex differences in how they influence depressive symptoms and inflammation, particularly when sex and gender differences are considered. The third study explores how diagnosis timing of major depressive disorder affects the associations between childhood maltreatment, C-reactive protein, and depressive symptoms. Analyses from the third study indicate that the inflammatory effects associated with childhood maltreatment could be reduced through the identification of major depression by health care providers, underscoring the need for effective screening are referral to services. A chapter is devoted to each study within the dissertation. A final chapter concludes the dissertation with a summarization of findings and discussion of implications for social work research and practice.