Background <p>Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of head and neck with high incidence and poor prognosis. Curcumin, as a drug–food congener, has a broad spectrum of anticancer effects, and based on this property, we further focused on EF24, a small molecule compound using curcumin as a backbone, to study the effects of both in OSCC.</p> Methods <p>Cell experiments were performed to test the inhibitory effect of curcumin and EF24 on OSCC cells. The potential mechanism was further analyzed by transcriptome sequencing, and the DEGs after drug treatment were determined. PPI networks were created using Cytoscape software.</p> Results <p>Both curcumin and EF24 inhibit the viability, migration, and invasion, and induce apoptosis of OSCC cells and the IC₅₀ of EF24 was much lower than that of curcumin. Analysis of DEGs identified 893 DEGs following curcumin treatment, of which 794 were up-regulated and 99 were down-regulated; 797 DEGs following EF24 treatment were identified, of which 665 were up-regulated and 132 were down-regulated. Curcumin and EF24 were found to down-regulate lipid metabolism by key enzymes that regulate fatty acid and cholesterol synthesis. Furthermore, the number of T cell CD4 + memory is up-regulated and the immune response is enhanced.</p> Conclusions <p>It is suggested that curcumin and EF24 inhibit the metabolic reprogramming of tumor cells and at the same time regulate TME, and improve the immunotherapy of tumors, which opens the way for the future treatment of OSCC with this approach alone or in conjunction with immune-checkpoint blocking.</p>