Background: The utilization of biomarkers is a way to assess the efficacy of recently created anticancer drugs. MiRNAs, telomerase, and Bcl-2 are extensively utilized as biomarkers for this purpose. This study aims to evaluate the comparison of the newly synthesized platinum compounds such as Platinum Azidothymidine (Pt-AZT) with Platinum Levetiracetam (Pt-Lev) on HepG2 cancer cell lines via the biomarkers. Methods: In this study, cells were divided into four groups: Group A (HDF cells) were the normal negative control group, group B were HepG2 untreated cancer cells, and groups C and D were treated cancer cells with Pt-AZT and Pt-Lev, respectively. After evaluating the LC50 for the drugs by MTT test, the relative gene expression of the biomarkers was determined by qPCR. Results: The results showed a significant decrease for antiapoptotic genes including miRNA-21 (5. 1±0. 014), telomerase (0. 56±0. 48), Bcl-2 (0. 41±0. 276) in group D, whereas in group C was more than group D for miRNA-21 (6. 0±0. 141), telomerase (3. 49±0. 231), Bcl-2 (4. 93±0. 276) also there was a significant increase in miRNA-122 (33. 97±0. 04) in group D, whereas in group C was (28. 36±0. 007) and so lower than group D. Most of the investigated groups showed a significant difference (p<0. 05). In addition, there were widespread apoptotic regions in Pt-Lev treatment compared to Pt-AZT. Conclusion: The advantages of using Pt-Lev were more powerful anticancer effects on biomarkers through inhibition of antiapoptotic and stimulation proapoptotic factors and also lower side effects and lower drug resistance than Pt-AZT,therefore, it can be considered a more effective anti-cancer therapy.