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Currently, many challenges are associated with hepatocellular carcinoma (HCC) as the failure of early diagnosis, and the lack of effective therapy. This study aimed to investigate the possible role of tuftelin 1 (TUFT 1) in the early diagnosis of HCC and evaluate the potential contribution of the TUFT 1/Ca+2/phosphinositol 3 kinase (PI3K) pathway in dantrolene sodium (Dan) therapeutic outcomes. The study was performed on two sets of rats, the staging (30 rats) and treatment sets (80 rats). HCC was induced by a single dose of diethylnitrosamine (DENA). The hepatic content of TUFT 1 protein was assayed via western blot and immunohistochemistry (IHC), while PI3K, vascular endothelial growth factor (VEGF), Cyclin D1, and matrix‐metalloproteinase‐9 (MMP‐9) contents were assessed using enzyme‐linked immunosorbent assay. Hepatic and serum calcium were measured colorimetrically. Furthermore, the nuclear proliferation marker, (Ki‐67), (Kiel [Ki] where the antibody was produced in the University Department of Pathology and the original clone number is 67)—expression was assessed by IHC. TUFT 1/Ca+2/PI3K signaling pathway was progressively activated in the 3 studied stages of HCC with subsequent upregulation of angiogenesis, cell cycle, and metastasis. More interestingly, Dan led to TUFT 1/Ca+2/PI3K pathway disruption by diminution of the hepatic contents of TUFT 1, calcium, PI3K, VEGF, Cyclin D1, and MMP‐9 in a dose‐dependent pattern. TUFT 1 can serve as a theranostic biomarker in HCC. Moreover, Dan exerted an antineoplastic effect against HCC via the interruption of TUFT 1/Ca+2/PI3K pathway. Significance statement: We investigated the role of tuftelin 1 (TUFT 1) TUFT 1/Ca+2/phosphinositol 3 kinase (PI3K) pathway in giagnosis, staging and dantrolene sodium (Dan) therapy. Hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DENA). TUFT 1/Ca+2/PI3K signaling pathway was progressively activated during stages of HCC with upregulation of angiogenesis, cell cycle, and metastasis. Dan led to TUFT 1/Ca+2/PI3K pathway disruption by depressing the hepatic contents of TUFT 1, calcium, PI3K, vascular endothelial growth factor, Cyclin D1, and metalloproteinase 9 in a dose‐dependent pattern. TUFT 1 can serve as a theranostic biomarker in HCC and Dan showed a promising antineoplastic effect against HCC via the interruption of TUFT 1/Ca+2/PI3K pathway. [ABSTRACT FROM AUTHOR]