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Background: Stem cell-like properties in cancer cells are found to be responsible for its aggressive behaviour. However, this has not been studied with respect to the bimodal NOTCH-pathway-activity status, found in oral cancer. Methods:Oral-SLCCs were enriched in 3D-spheroids. Constitutively-active and inactive status of NOTCH-pathway was achieved by genetic or pharmacological approaches. RNA sequencing and real-time PCR was performed for gene expression studies. in vitro cytotoxicity assessments were performed by AlamarBlue assay and in vivoeffects were studied by xenograft growth in zebrafish embryo. The t tests were performed to estimate statistical significance of the study. Results: Here, we have demonstrated the stochastic plasticity on NOTCH-activity axis; maintaining both NOTCH-active and inactive states of oral stem-like cancer cells (Oral-SLCCs). While Oral-SLCCs with inactive NOTCH-pathway status showed higher proliferation and aggressive tumor growth, the Cisplatin refraction was associated with active-status of NOTCH-pathway; suggesting the crucial role of plasticity on NOTCH-axis. The differentially expressed genes between NOTCH-pathway active and inactive clones clearly suggested the upregulation of JAK-STAT signaling in subset of Oral-SLCCs with lower NOTCH-pathway activity status. Confirming the function; the 3D-spheroids generated by oral-SLCCs with lower NOTCH-activity-status displayed significantly higher sensitivity to JAK-selective drugs, Ruxolitinib or Tofacitinib and siRNA mediated downregulation of tested partners STAT 3 and 4. Therefore, we adopted the strategy of synthetic lethality, where Oral-SLCCs were reprogrammed to maintain the inactive status of NOTCH-pathway by exposure to γ-secretase inhibitors, LY411575 or RO4929097 followed by targeting with JAK-inhibitors, Ruxolitinib or Tofacitinib. This resulted in a very significant inhibition in viability of 3D-spheroids as well as xenograft formation in Zebrafish embryos; whereas inhibition of either of these pathway alone were largely ineffective. Conclusion: We have demonstrated the stochastic cellular plasticity on NOTCH-activity axis. Study revealed for the first time that NOTCH-HES and JAK-STAT pathways may act as synthetic lethal pair, and as novel targets against diverse states of stemness in oral cancer. Therefore, we have provided the rational for sequential combination of NOTCH and JAK inhibitors as possible therapeutic strategy against aggressive oral cancer.