While depression associated with disability has been extensively studied, how depression could differ depending on whether the disability is congenital or acquired remains to be investigated. The objective of this study was to compare depression and related factors among people with congenital and acquired physical disabilities. We used the 2016 Panel Survey of Employment for the Disabled in Korea, a population-based survey for people with disability registered with the Korean government. Among 4577 participants, a total of 2128 participants with physical disability were analyzed using chi-square and binary logistic regression analysis. The prevalence of depression was 12.9% in those with congenital physical disability and 16.0% in those with acquired physical disability. Stress due to disability and family relationship satisfaction were associated with higher and lower odds of depression, respectively, in both disability groups. Discrimination due to disability, divorce, social participation, and subjective social status were significant predictors of depression only in people with acquired disability. Compared to those with congenital disability, individuals with acquired disability can be more susceptible to issues relating to social relationships, social standing and discrimination. Findings of this study suggest that acquired disability and adapting to changes associated with it can be a source of mental distress in addition to living with it. Efforts are needed to address discrimination, provide supportive social relationships, and provide supportive living conditions in order to reduce depression in persons living with disability, especially those with acquired disability.