In the context of ovarian cancer, 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR) exhibits promising anticancer activity; however, its poor aqueous solubility, low half-life, and adverse effects create major challenges for its application in cancer treatment. In the present study, we prepared AICAR-loaded nanoparticles surface conjugated with anti-EGFR monoclonal antibody (panitumumab) which yielded the required sustained release profile and enhanced nanoparticle uptake into SKOV3 cells. Panitumumab-conjugated AICAR-poly(lactic-co-glycolic acid) (PLGA)-NP (Pmab-AICAR-PLGA-NP) induced apoptosis in SKOV3 cells in an AMP-activated protein kinase (AMPK)-dependent manner to a significantly higher extent than AICAR-PLGA-NP. In addition, Pmab-AICAR-PLGA-NP disrupted the mitochondrial membrane potential, induced cleavage of caspases and poly (ADP-ribose) polymerase leading to cell death. Furthermore, STAT3 phosphorylation and expression of PD-L1 was suppressed. Our formulation substantially amplified the cytotoxic effects of AICAR on SKOV3 cells by modulating AMPK/STAT3 signaling. Thus, Pmab-AICAR-PLGA-NP can serve as a modular platform for the delivery of AICAR for the treatment of ovarian cancer.