Esophageal cancer (EC) incidence remains to be on a global rise supported by an unchanged recurrence and 5-year survival rate owing to the development of chemoresistance. Resistance to cisplatin, one of the majorly used chemotherapeutic drugs in EC, is a major nuisance. This study sheds light on miRNA dysregulation and its inverse relation with dysregulated mRNAs to guide pathways into the manifestation of cisplatin resistance in EC. A cisplatin-resistant version of an EC cell line was established and comparative profiling by NGS with the parental cell line was employed to identify dysregulation in miRNA and mRNA levels. Protein-protein interaction network analysis was done using Cytoscape, followed by Funrich pathway analysis. Furthermore, selective significant miRNAs were validated using qRT-PCR. miRNA-mRNA integrated analysis was carried out using the Ingenuity Pathway Analysis (IPA) tool. Expression of various established resistance markers supported the successful establishment of cisplatin-resistant cell line. Whole-cell small RNA sequencing and transcriptome sequencing identified 261 miRNAs and 1892 genes to be significantly differentially expressed (DE), respectively. Pathway analysis indicated enrichment of EMT signaling, supported by NOTCH, mTOR, TNF receptor, and PI3K-mediated AKT signaling pathways, in chemoresistant cells. Validation by qRT-PCR confirmed upregulation of miR-10a-5p, miR-618, miR-99a-5p, and miR-935 and downregulation of miR-335-3p, miR-205-5p, miR-944, miR-130a-3p, and miR-429 in resistant cells. Pathway analysis that followed IPA analysis indicated that the dysregulation of these miRNAs and their target genes may be instrumental in the development and regulation of chemoresistance via p53 signaling, xenobiotic metabolism, and NRF2-mediated oxidative stress. This study concludes the interplay between miRNA and mRNA as an important aspect and occurrence in guiding the regulation, acquisition, and maintenance of chemoresistance in esophageal cancer in vitro.