BACKGROUND: Recurrence after cisplatin therapy is one of the major hindrances in the management of cancer. This necessitates a deeper understanding of the molecular signatures marking the acquisition of resistance. We therefore modeled the response of osteosarcoma (OS) cells to the first-line chemotherapeutic drug cisplatin. A small population of nondividing cells survived acute cisplatin shock (persisters; OS-P). These cells regained proliferative potential over time re-instating the population again (extended persisters; OS-EP). RESULT: In this study, we present the expression profile of noncoding RNAs in untreated OS cells (chemo-naive), OS-P, OS-EP and drug-resistant (OS-R) cells derived from the latter. RNA sequencing was carried out, and thereafter, differential expression (log2-fold ± 1.5; p value ≤ 0.05) of microRNAs (miRNAs) was analyzed in each set. The core set of miRNAs that were uniquely or differentially expressed in each group was identified. Interestingly, we observed that most of each group had their own distinctive set of miRNAs. The miRNAs showing an inverse correlation in expression pattern with mRNAs were further selected, and the key pathways regulated by them were delineated for each group. We observed that pathways such as TNF signaling, autophagy and mitophagy were implicated in multiple groups. CONCLUSION: To the best of our knowledge, this is the first study that provides critical information on the variation in the expression pattern of ncRNAs in osteosarcoma cells and the pathways that they might tightly regulate as cells acquire resistance.