Objective: The aim of this study was to evaluate the diagnostic accuracy of conventional CT values and the dual-energy computed tomography (DECT)-derived effective atomic number (Zeff), fat fraction (FF) and iodine concentration (IC) for the differentiation of hypodense liver lesions in patients with colorectal cancer (CRC). Methods: One hundred and twenty patients (mean age: 65 ± 12 years) affected by CRC who underwent dual-source DECT as part of tumor staging between December 2015 and June 2023 were retrospectively evaluated. Spectral datasets were reconstructed for each patient and regions of interest were applied at the level of hypodense liver lesions to collect CT, Zeff, FF and IC values. To assess diagnostic accuracy, receiver operating characteristic (ROC) curves were constructed to evaluate the area under the curve (AUC), sensitivity, and specificity using biopsy or MRI (in cases when biopsy was not indicated or feasible) as a reference standard. The Youden index was used to identify optimal cut-off values for potential clinical applications. Results: A total of 223 lesions (147 metastases and 76 cysts) were evaluated. CT, FF and IC values differed significantly between metastases and cysts (p < 0.0001), showing high diagnostic accuracy. FF showed significantly higher diagnostic accuracy compared to all other parameters (all p ≤ 0.0074), with an AUC value of 0.97 (95% CI: 0.94–0.99). For a cut-off > 15.9, the sensitivity reached 91.8% (95% CI: 86.2–95.7) and the specificity reached 98.7% (95% CI: 92.9–100). Zeff numbers did not differ considerably (p = 0.781) between the two entities and demonstrated a lower AUC (0.511; 95% CI: 0.44–0.58). Conclusions: FF measurements proved to have high diagnostic accuracy compared to CT values, IC, and Zeff in the evaluation of hypodense liver lesions in patients suffering from colorectal carcinoma.