Objective: Substance use disorder (SUD) is a serious public health problem affecting both the individual and the society, and substance use-related deaths and disability have been shown to increase gradually. Recent etiologic studies have reported that there is a relation between inflammatory parameters and psychiatric disorders. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) used as an indicator of inflammation have been shown to be increased in various psychiatric disorders. In this study, we aimed to investigate the NLR and PLR in adolescents with SUD. Methods: This study was conducted by retrospectively examining the records of 55 male adolescents who were followed up with SUD in a child and adolescent psychiatry outpatient clinic between November 2019−June 2020. Patients who had comorbid psychiatric disorder were included, and those who received any psychotropic medication were excluded. A total of 61 healthy male adolescents in the same age range without any psychiatric disorders were recruited as a control group. Neutrophil-lymphocyte-platelet counts were noted retrospectively from complete blood tests, and NLR-PLR were calculated. Results: The NLR and PLR of adolescents with SUD were significantly higher than the healthy adolescents (p ＜ 0.01, p ＜ 0.01, respectively). In addition, conduct disorder, depression, and attention deficit/hyperactivity disorder, which were determined as the most common comorbid psychiatric disorders had no effects on NLR (p = 0.513, p = 0.584, p = 0.394, respectively) and PLR (p = 0.210, p = 0.346, p = 0.359, respectively). Conclusion The results of current study indicate that inflammatory processes may have a key role in the pathophysiology of SUD.