Background: Preterm birth (PTB) forms the prime etiology of mortality and morbidity in neonates worldwide. Our study compares serum epigenetic 548ai] and proteomic profiling [interleukin-6 (IL-6), alpha-fetoprotein (AFP)] in prediction of preterm birth. Materials and methods: Blood was drawn from 88 pregnant women at 19-26 weeks of gestation who were followed until delivery. The concentrations of miR-150-5p, miR-223-3p, miR-302b-3p, and miR-548ai (Real-time polymerase chain reaction-RT-PCR) were compared with IL-6 and AFP [enzyme-linked immunosorbent assay (ELISA)]. Results: Our study had 75 term and 13 preterm deliveries. A "p" value of 0.003 for birth weight and preterm delivery; statistically noteworthy was appreciated. Upregulation of miR-150-5p, miR-223-3p, miR-302b-3p was seen in preterm patients with p-value of 0.021, 0.060, and 0.062, respectively. The area under the ROC curve (AUC-ROC) analysis for miR-150-5p (0.739) showed 46.15% sensitivity with 100% specificity and positive predictive value (p-value = 0.0042). miR-302b-3p had the highest sensitivity and negative predictive value of 84.6 and 96.1%, respectively. miR-223-3p defined a 100% positive predictive value and specificity. miR-548ai had 69.23% sensitivity, 44% specificity and p-value = 0.6884 (AUC-ROC). The IL-6 and AFP levels were not significantly different between two delivery groups (p-value = 0.466 and 0.399). Conclusion: miR-150-5p is an effective epigenetic biomarker for prediction of preterm labor compared to IL-6 and AFP. miR-223-3p, miR 302b-3p levels are upregulated in preterm women.