Diabetes mellitus and chronic liver disease often coexist in long-term disease progression causing adverse outcomes and premature mortality. Furthermore, diabetes and metabolic syndrome exhibit a closed interlinking mechanism with hepatitis, liver cirrhosis, liver cancer through the glucose and metabolic homeostasis imbalance. However, the association with acute-on-chronic liver failure (ACLF) has been poorly studied in the last years. Therefore, we aimed to investigate the association of diabetes mellitus and metabolic syndrome (DM/MS) with ACLF patients, to use it as a disease prognostic indicator. A total of 34 consecutive ACLF patients above 18 years were included, as well as their clinical records, and divided into DM/MS and non-DM/non-MS groups. They were tested for anthropometric and biochemical assays and all data was analysed to assess the immediate and short-term progression. We observed that DM/MS patients had increased numbers in the different demographic clinical variables, had increased levels in their glucose and lipid profile, and reduced levels in their protein profile, with respect to the control group non-DM/non-MS. About death occurrence, we observed an increase in DM/MS group (33.3%) respect to the control group (15.78%). With these results, we can infer that ACLF patients with DM/MS have a higher risk of mortality and a longer period of stay in the hospital. The coexistence of DM and MetS in ACLF patients is associated with increased disease severity, worse prognosis, and adverse outcomes. Timely recognition and appropriate management of these comorbidities are crucial to improve patient outcomes.