Background: Acute myeloid leukemia (AML) remains an aggressive hematologic malignancy in which resistance to apoptosis limits the efficacy of standard chemotherapy. MicroRNA-222 (miR-222) has been implicated in leukemic cell survival and proliferation, and its inhibition may sensitize AML cells to cytotoxic treatment. Objective: To evaluate whether inhibition of miR-222 enhances the anti-leukemic effect of cytarabine in HL-60 cells and to determine associated changes in apoptosis-related and AML-relevant gene expression. Methods: HL-60 cells were transfected with locked nucleic acid anti-miR-222 (LNA-anti-miR-222). Following pilot optimization of cytarabine concentration (IC50 1.8 μM) and LNA dose (50 pmol selected from 10-100 pmol titration), cells were assigned to five groups: untreated control, scrambled LNA control, cytarabine alone (1 μM), LNA-anti-miR-222 alone (50 pmol), and LNA-anti-miR-222 plus cytarabine. A 3×3 concentration-response matrix was also tested. Relative miR-222 expression was quantified by SYBR Green real-time PCR using U6 normalization. Cell viability was assessed by MTT assay at 72 hours. Apoptosis was evaluated by Annexin V/7-AAD flow cytometry at 48 hours. Expression of BAX, BCL-2, MCL-1, WT1, C-KIT, and CEBPA was measured by real-time PCR (GAPDH normalization). Statistical comparisons for qPCR were performed on ΔCt values. Results: LNA-anti-miR-222 effectively suppressed miR-222 expression in HL-60 cells (by approx. 74%, p<0.01). Cytarabine alone reduced cell viability to 68.3% and induced 19.4% total apoptosis, whereas miR-222 inhibition alone reduced viability to 51.6% and induced 27.5% apoptosis. The combination of LNA-anti-miR-222 and cytarabine produced the greatest reduction in viability (29.8%) and the highest apoptotic fraction (48.6%, p<0.001 vs either alone). A 3×3 concentration matrix confirmed the robustness of the enhanced effect across multiple doses, and two-way ANOVA revealed a significant interaction between the two agents (p=0.008). Combination treatment was associated with marked upregulation of BAX (4.1-fold), downregulation of BCL-2 (0.31-fold) and MCL-1 (0.52-fold), and substantial suppression of C-KIT expression (0.23-fold). WT1 showed a modest decrease (0.71-fold), whereas CEBPA did not change significantly. Conclusion: Inhibition of miR-222 enhanced the cytotoxic and pro-apoptotic activity of cytarabine in HL-60 cells across a range of concentrations. These findings support miR-222 as a potential therapeutic target in AML and suggest that miR-222 blockade may improve chemosensitivity, pending protein-level validation of the proposed mechanisms.