Background: There is no gold standard tool to definitively diagnose sepsis and no consistent system to predict outcomes. In any clinical setup, laboratory biomarkers are very important and can serve in determining the suitable treatment course. Serum lactate is one of these biomarkers that is known to be linked with mortality in patients with sepsis. Even procalcitonin (PCT) has been said to be a biomarker very useful in diagnosing sepsis. C-reactive protein (CRP) is an acute phase reactant and another sensitive marker of sepsis. Materials and methods: A prospective observational study was conducted in a tertiary care center in Jaipur, Rajasthan, India, including 160 study participants who were admitted to the intensive care unit (ICU) and diagnosed with sepsis. Detailed history and examination were made, followed by blood investigations. Written informed consent was obtained from all participants, and Institutional Ethics Committee approval was taken at the beginning of the study. Statistical analysis was done after adequate data collection. Results: Mean CRP (mg/L) was 9 ± 1.41, mean PCT (ng/mL) was 1.6 ± 0.56, and mean lactate (mmol/L) was 2.1 ± 1.97 among the study subjects. Mean CRP was found to be significantly higher in expired subjects (77 ± 31.1) as compared to survivors (9 ± 1.41). This difference was statistically significant as p < 0.05. Mean PCT (ng/mL) was found to be significantly higher in expired subjects (11.1 ± 0.14) as compared to survivors (1.6 ± 0.56). This difference was statistically significant as p < 0.05. Mean serum lactate was found to be higher in expired (3.4 ± 0.77) subjects as compared to survivors (2.1 ± 1.97), but this difference was not statistically significant as p > 0.05. Conclusion: The combined biomarker approach using CRP, PCT, and lactate depicted a better performance in predicting 28-day mortality.