Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. Non-invasive assessment of hepatic disease severity represents a relevant issue to further improve clinical management and therapeutic treatment. We retrospectively compared the diagnostic and prognostic performance of different non-invasive tools (LiMAx, transient elastography (TE), and biomarkers) in detecting different severity stages during the course of CLD. Patients were divided into four groups based on clinical parameters: (1) patients without CLD (control group), (2) patients suffering from CLD without having cirrhosis, (3) patients with CLD and compensated cirrhosis, and finally, (4) patients with CLD and decompensated cirrhosis. Patients with acute liver failure were excluded from the analysis. A total of 464 patients who underwent LiMAx measurement at the University Clinic of Essen between 10/2016 and 11/2017 were included in this study. Distribution of the different groups were n = 72 patients for group 1, n = 134 patients for group 2, n = 160 patients for group 3, and n = 98 patients for group 4, respectively. Median LiMAx values significantly declined with respect to increasing degree of CLD: (1) 510 µg/h/kg, (2) 390 µg/h/kg, (3) 264 µg/h/kg, and (4) 151 µg/h/kg (p < 0.001). When comparing the diagnostic accuracy of the LiMAx test in detecting patients with presence of cirrhosis (groups 1 and 2 vs. groups 3 and 4), an AUROC of 0.942 was found (cut-off 322 µg/h/kg, sensitivity 86.1%, specificity 91.3%, p < 0.0001). LiMAx was superior to TE and serum biomarkers in predicting patients’ outcome by 90-day mortality (AUROC 0.811, p < 0.001). Enzymatic liver function measured by LiMAx was closely associated with different severity stages of CLD and was a reliable diagnostic and prognostic tool with an accuracy comparable to current standard methods.