Tobacco kills their half of the consumers still, grown as the most lucrative crop worldwide for different uses like chewing, smoking, and snuffing. On the other side, it was known as a chief medicinal plant by Native Americans, ancient European, Amazonian and Indian. In the middle 20th century tobacco was declared a negative and hazardous plant because of its nicotine component. Nicotiana tabacum (N. tabacum) is well studied in plant biotechnology and studied as a model plant. Likewise. N. tabacum miRNAs were also identified a decade ago however a genome-wide computational approach to identify miRNAs remained to be explored. These XenomiRs and their cross-species talk were also revealed for the first time in the current study. The top ten hub nodes (CCNE1, DDX5, NEUROD1, SOS1, CUL2, OPHN1, SOX9, KCNA1, FBXW2, and NOC3L) were retrieved from the experiment which gives evidence of tobacco miRNAs and their involvement in diseases like carcinoma and neurodevelopmental disorders.