Background Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited effective systemic treatments and a high incidence of therapeutic resistance. Increasing evidence 71implicates dysregulation of the PI3K/AKT/mTOR signaling pathway as a critical driver of tumor progression, metabolic reprogramming, and drug resistance in HCC. However, data from Eastern European populations remain scarce. This study aimed to evaluate the expression and activation status of PI3K/AKT/mTOR pathway components in Romanian HCC patients and assess their association with clinicopathologic features, survival, and resistance to systemic therapy. Methods A prospective observational study was conducted on 92 patients with histologically confirmed HCC treated at the Fundeni Clinical Institute (2021–2024). Tumor and matched non-tumor liver tissues were analyzed by immunohistochemistry (IHC) and Western blot for PI3K, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and PTEN. Quantitative H-scores and densitometric analyses were correlated with clinicopathologic variables and patient outcomes. Drug resistance markers (MDR1, BCL-2) were assessed in patients receiving sorafenib or lenvatinib. Survival analyses were performed using Kaplan–Meier and Cox proportional hazards models. Results Strong activation of the PI3K/AKT/mTOR pathway was observed in tumor tissue compared with adjacent liver (p < 0.001). Mean H-scores were significantly higher for p-AKT (173 ± 39 vs. 65 ± 25) and p-mTOR (167 ± 35 vs. 59 ± 23), while PTEN expression was reduced (72 ± 30 vs. 188 ± 41; p < 0.001). High p-AKT and p-mTOR expression correlated with tumor size >5 cm, microvascular invasion, high AFP levels, and advanced BCLC stage (p < 0.01). Among patients treated with systemic therapy (n = 38), 55.3% developed drug resistance within six months, showing increased p-AKT, p-mTOR, and MDR1/BCL-2 expression (p < 0.001). In multivariate analysis, high p-AKT (HR 2.47, 95% CI 1.33–4.59), high p-mTOR (HR 2.16, 95% CI 1.12–3.98), PTEN loss (HR 1.82, 95% CI 1.03–3.21), and sorafenib resistance (HR 2.59, 95% CI 1.41–4.23) were independent predictors of poor overall survival. Median overall survival was 15.6 months in patients with high p-AKT expression versus 30.3 months in low-expression cases (p = 0.002). Conclusions Aberrant activation of the PI3K/AKT/mTOR pathway is a major molecular event driving tumor aggressiveness and therapeutic resistance in Romanian hepatocellular carcinoma. Overexpression of p-AKT and p-mTOR and loss of PTEN are independently associated with poor prognosis and early resistance to multikinase inhibitors. These results underscore the potential clinical utility of incorporating PI3K/AKT/mTOR biomarkers into diagnostic and therapeutic stratification algorithms for HCC. Targeted inhibition of this pathway, alone or combined with MAPK or immune checkpoint blockade, represents a promising strategy for overcoming drug resistance and improving survival outcomes.