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<i>Background and Objectives</i>: Differentiating between hypovolemic (HH) and euvolemic hyponatremia (EH) is crucial for correct diagnosis and therapy, but can be a challenge. We aim to ascertain whether changes in serum creatinine (SC) can be helpful in distinguishing HH from EH. <i>Materials and Methods</i>: Retrospective analysis of patients followed in a monographic hyponatremia outpatient clinic of a tertiary hospital during 1 January 2014–30 November 2019. SC changes during HH and EH from eunatremia were studied. The diagnostic accuracy of the SC change from eunatremia to hyponatremia (∆SC) was analyzed. <i>Results</i>: A total of 122 hyponatremic patients, median age 79 years (70–85), 46.7% women. In total, 70/122 patients had EH, 52/122 HH. During hyponatremia, median SC levels increased in the HH group: +0.18 mg/dL [0.09–0.39, <i>p</i> < 0.001], but decreased in the EH group: −0.07 mg/dL (−0.15–0.02, <i>p</i> < 0.001), as compared to SC in eunatremia. HH subjects presented a higher rate of a positive ∆SC than EH (90.4% vs. 25.7%, <i>p</i> < 0.001). EH subjects presented a higher rate of a negative/null ∆SC than HH (74.3% vs. 9.6%, <i>p</i> < 0.001). ROC curve analysis found an AUC of 0.908 (95%CI: 0.853 to 0.962, <i>p</i> < 0.001) for ∆SC%. A ∆SC% ≥ 10% had an OR of 29.0 (95%CI: 10.3 to 81.7, <i>p</i> < 0.001) for HH. A ∆SC% ≤ 3% had an OR of 68.3 (95%CI: 13.0 to 262.2, <i>p</i> < 0.001) for EH. <i>Conclusions</i>: The assessment of SC changes from eunatremia to hyponatremia can be useful in distinguishing between HH and EH.