Background and Objectives: Brain-derived neurotrophic factor (BDNF), best known for its role in cognitive function, is an anti-inflammatory protein proposed as a potential therapeutic target and diagnostic biomarker in sepsis. However, studies investigating circulating BDNF levels in patients with sepsis have yielded conflicting results, reporting both increased and decreased concentrations. Comorbid conditions, particularly liver cirrhosis, pancreatitis, and kidney failure, may contribute to these discrepancies. Therefore, the primary aim of this study was to investigate the association between plasma BDNF levels and these comorbidities in patients with sepsis. Materials and Methods: Plasma BDNF concentrations were measured in 250 critically ill patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock and 40 healthy controls. Among these patients, 56 had liver cirrhosis, 44 had pancreatitis, and 94 required dialysis. Results: Patients with SIRS/sepsis/septic shock exhibited significantly lower plasma BDNF levels than healthy controls. Plasma BDNF concentrations were unchanged in patients with concomitant liver cirrhosis, increased in the 44 patients with pancreatitis, and significantly decreased in those with acute kidney injury requiring dialysis (AKI-D), compared with patients without pancreatitis and those without AKI-D, respectively. When patients were stratified by dialysis status, plasma BDNF levels were similar among patients with SIRS, sepsis, and septic shock. Plasma BDNF levels did not change in ventilated patients or in those who did not survive. Furthermore, patients with COVID-19-related sepsis and those with non-COVID-19 etiologies showed comparable plasma BDNF concentrations. However, plasma BDNF levels in non-dialysis and dialysis patients were not, or were only weakly, associated with routine measures of renal function. Plasma BDNF levels positively correlated with platelet count, which predicted BDNF levels in patients with SIRS/sepsis/septic shock. Conclusions: Plasma BDNF levels are similarly reduced in patients with SIRS/sepsis/septic shock and are further decreased in AKI-D, whereas patients with pancreatitis exhibit higher BDNF levels. Platelet count, which decreased in AKI-D and was higher in pancreatitis, predicted plasma BDNF levels, suggesting platelet count as an important factor affecting plasma BDNF levels.