Albumin is a metal-binding protein with free-radical scavenging properties and is recognized as a vital antioxidant. Moreover, an excess of free radicals may contribute to depressive symptoms and the psychopathology of psychiatric disorders. This study examined serum albumin levels, depressive symptoms, and their association in patients with schizophrenia. Thirty-four patients with schizophrenia (diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition) and 136 healthy controls were consecutively enrolled in this case-control study. The clinical psychiatric symptoms in patients with schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS). Serum albumin levels were measured in all participants using an immunoturbidimetric method. This study was conducted between 2016 and 2017. Serum albumin levels were significantly lower in patients with schizophrenia compared to healthy controls after adjusting for gender, age and education (F = 16.04, p = 0.000). Serum albumin levels were negatively correlated with the depressive score of PANSS in patients with schizophrenia (r = −0.37, p = 0.03). Additionally, a further stepwise multivariate regression analysis showed that serum albumin levels were significantly associated with the depressive score of PANSS in patients with schizophrenia (ß = −0.37, t = −2.25, p = 0.03). Our data suggested that decreased serum albumin levels may contribute to the psychopathology of schizophrenia and that a decline in serum albumin levels was associated with the severity of depressive symptoms in patients with schizophrenia.