Number of annual deaths due to cancer is dramatically increasing despite the advances in the treatment strategies. Boswellic acids are natural active constituents of resins obtained from the genus Boswellia. New series of 11- keto-β-boswellic acids (AKBA) were partially-synthesized by modifying the hydroxyl and carboxylic acid functional groups of ring A. The most active compounds of this series gave IC50 values as low as 9.6m M using two different human tumor cell lines. The results revealed that the selectivity of natural AKBA was higher than new derivatives with IC50 value of 1014 μM and EC50 dose of 1006 μM when tested on normal epithelial cell lines. Additionally, a maximum nuclear fragmentation was observed for compound 4 (78.44%) in treated cells after 24 hours followed by compounds 5 and 9 with (74.25 and 66.9% respectively). This study suggests that the presence of a hydrazone functionality (compounds 4 and 9) has effectively improved the potency of AKBA. Interestingly, compound 5 with a lost carboxylic acid group of ring A showed comparable potent activity. Highly selective AKBA requires further modification to improve its bioavailability and solubility inside the cancer cells. Proteomic profiling of AKBA-treated cells revealed a novel role of AKBA in cancer treatment via induction of mitophagy through upregulation of SQSTM1 protein. Mitophagosomes and mitochondrial abnormalities were shown in AKBA -treated cells. Increased SQSTM1 protein levels was not mediating via alteration in proteosomal degradation. This suggests that AKBA increases SQSTM1 levels at gene transcription levels and not at translation and post- translation levels In conclusion; Derivatization of AKBA does not enhance the potency and selectivity, thereby, further investigation to improve its bioavailability and solubility inside the cancer cells is highly recommended. We provided novel evidence that AKBA-induced apoptosis of cancer cells by initiating mitophagy pathway through targeting SQSTM1 protein expression. Our findings could provide a rationale for further investigation of this valuable compound in chemoprevention and/or treatments in cancer disease.