Impressed by the exceptional anticancer activity of cinnamon, the present study was conducted to elucidate the anticancer potential of essential oil of Cinnamon (EOC). EOC was tested against various cell lines (FaDu, Detroit-562 and SCC-25) of head and neck squamous cell carcinoma (HNSCC) using MTT assay. The Hep-2 cell xenograft model was used to assess the positive bio-activity of EOC. EGFR-TK inhibitory assay was also carried out to explain the possible mechanism of action of EOC. Moreover, to rationalise the key contacts responsible for attenuating EGFR, the major component of EOC, i.e., trans-cinnamaldehyde, as identified by GC-MS analysis, was subjected to molecular docking experiments with the catalytic domain of EGFR protein model. EOC exhibited significant anticancer activity with percent inhibition 66.12, 87.32, and 99.34%, against FaDu, Detroit-562 and SCC-25, respectively. Moreover, EOC reduced the tumor burden to 43.5% in Hep-2 cell xenograft model along with 89% inhibition of EGFR-TK activity in the EGFR-TK inhibitory assay. Docking experiments showed that trans-cinnamaldehyde was proficiently fitted into the inner grove of the active site of EGFR by making close inter-atomic contacts with the key catalytic residues Val702, Ala719, Lys721, Leu764, Thr766 and Leu820 and with inhibition constant Ki = 775.93 μM. EOC exhibits significant anticancer activity against HNSCC cells in vitro. The mechanism underlying its anticancer action was attributed to the suppression of EGFR-TK. It also significantly suppressed the tumor growth in Hep-2 cell xenograft model.