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Sepsis is a life-threatening complication among patients with liver cirrhosis and is associated with high morbidity and mortality. Early diagnosis is challenging due to immune dysfunction, chronic systemic inflammation, and overlap between clinical and laboratory findings during infection and hepatic decompensation. Therefore, there is a need to identify routinely available predictors that may enable the stratifying of patients at risk of developing sepsis in this population and facilitate intensive monitoring, antibiotic treatment, and potentially reduce mortality. The aim of this study is to evaluate the association between routine laboratory parameters and the development of sepsis among cirrhotic patients. A total of 171 cirrhotic patients met the inclusion criteria and were followed at a tertiary liver clinic between February 2015 and February 2022. Sepsis was defined according to Sepsis-3 criteria. Univariate analyses were performed to compare sepsis patients versus non-sepsis patients. Multivariable logistic regression was conducted to identify independent predictors of sepsis. Among 171 patients, 41 (24%) developed sepsis and 130 (76%) did not. Baseline characteristics were similar between groups: patients with sepsis were slightly older (67.5 ± 10.9 vs. 64.5 ± 12.3 years, p = 0.172), with no significant differences in sex (53.7% vs. 56.2%, p = 0.78) or ethnicity (Arab ethnicity 56.1% vs. 39.1%, p = 0.055). Ascites was more frequent in the sepsis group (53.7% vs. 26.2%, p = 0.001), whereas esophageal varices were less common (12.2% vs. 35.4%, p = 0.006). Rates of hepatic encephalopathy and acute kidney injury did not differ significantly. Higher creatinine (1.35 (0.80–3.35) vs. 0.80 (0.70–1.49) mg/dL, p < 0.001), INR (1.50 (1.20–1.80) vs. 1.30 (1.10–1.50), p = 0.011), and total bilirubin (1.90 (0.61–2.85) vs. 0.90 (0.59–1.70) mg/dL, p = 0.049) was observed in the sepsis group. In the multivariable model including age, sex, ethnicity, ascites, esophageal varices, INR, creatinine, neutrophil-to-lymphocyte ratio, and CRP, baseline serum creatinine was the only independent predictor of sepsis (adjusted OR 1.58 per 1 mg/dL increase, 95% CI 1.08–2.33, p = 0.01). Receiver operating characteristic (ROC) analysis demonstrated that the multivariable model had acceptable discriminative ability for prediction of sepsis, with an area under the curve (AUC) of 0.741 (95% CI 0.647–0.835). Among ambulatory patients with liver cirrhosis, baseline serum creatinine was independently associated with the development of sepsis. These findings highlight the need for dedicated risk-stratification tools in the outpatient setting. Further external validation in independent cohorts is required.