Non-small cell lung cancer (NSCLC) is a deadly kind of cancer that contributes significantly to the global cancer mortality rate. It is distinguished by a significant level of malignancy and unfavourable prognosis. The molecular pathways responsible for tumour invasion and migration in NSCLC are not fully understood, despite their widespread occurrence and significant consequences. Moreover, the ability of cancer cells to withstand the effects of chemical treatments presents a substantial obstacle in the creation of successful treatment approaches for NSCLC. Annona muricata Linn (A. muricata) is known to possess powerful anticancer bioactive components. A. muricata extracts have demonstrated significant therapeutic potential among a wide range of botanical compounds. However, the specific molecular interactions of the plant have not yet been revealed. This study aims to evaluate the anticancer potential of A. muricata leaves extracts on the NSCLC cell line and compare the efficacy of two different extraction methods, namely maceration extraction (ME) and ultrasonic-assisted extraction (UAE). Results showed that ME demonstrated significantly higher antioxidant activity compared to UAE, with respective percentages of 81.4% and 29.4%. However, the UAE extract demonstrated more pronounced cytotoxic effects on the NSCLC cell line (HLFa) with an IC50 value of 139.6 µg/ml, indicating a stronger antiproliferative effect on cancer cell. Both ME and UAE extracts reduced nitrite release in HLFa cell supernatants, with the ME extract showing superior activity. Treatment with ME and UAE also resulted in the activation of Caspase3/7, indicating the induction of apoptosis in HLFa cells compared to the untreated control. The extracts and Cisplatin differ approximately 0.3-fold in caspase 3/7 activation though it was not statistically significant. This activation suggests that both extraction methods effectively initiate the apoptotic cascade which is crucial for the elimination of cancer cells. Furthermore, the UAE extract significantly reduced BCL-2 mRNA levels (p<0.05). The significant reduction in BCL-2, a protein that prevents apoptosis reflect the extract’ ability to modulate key apoptotic regulators with the most significant activity when UAE extracts were used. In summary, A.muricata leaves extracts obtained through both ME and UAE methods exhibited promising anticancer effects against NSCLC, with UAE extracts exhibiting superior activity. These findings pave the way for further investigations into the use of A.muricata in cancer treatment and the development of new therapeutic agents based on its properties.