Heat-shock factor 1 (HSF1) is a multifunctional transcription factor whose overexpression is associated with the development, progression, and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). In the present study, we thoroughly investigated the antitumor activity of NXP800, a recently developed HSF1 inhibitor that is currently tested in clinical trials, on HCC growth. We discovered that NXP800 inhibits the cell growth of human HCC cell lines by reducing proliferation, inducing apoptosis, and causing DNA damage. At the metabolic level, NXP800 significantly decreased mitochondrial respiration, which was associated with extensive structural alterations in the mitochondria, and reduced glycolysis of HCC cells. At the molecular level, NXP800 administration led to the upregulation of the integrated stress response and downregulation of the E2F1 signaling cascade. In addition, NXP800 profoundly constrained the growth of HCC patient-derived organoids. Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC.