Cancer cells can adapt to their surrounding microenvironment by upregulating glucose-regulated protein 78 kDa (GRP78) and vacuolar-type ATPase (V-ATPase) proteins to increase their proliferation and resilience to anticancer therapy. Therefore, targeting these proteins can obstruct cancer progression. A comprehensive computational study was conducted to investigate the inhibitory potential of four proton pump inhibitors (PPIs), dexlasnoprazole (DEX), esomeprazole (ESO), pantoprazole (PAN), and rabeprazole (RAB), against GRP78 and V-ATPase. Molecular docking revealed high-affinity scores for PPIs against both proteins. Moreover, molecular dynamics showed favorable root mean square deviation values for GRP78 and V-ATPase complexes, whereas root mean square fluctuations were high at the substrate-binding subdomains of GRP78 complexes and the alpha-helices of V-ATPase. Meanwhile, the radius of gyration and the surface-accessible surface area of the complexes were not significantly affected by ligand binding. Trajectory projections of the first two principal components showed similar motions of GRP78 structures and the fluctuating nature of V-ATPase structures, while the free-energy landscape revealed the thermodynamically favored GRP78-RAB and V-ATPase-DEX conformations. Furthermore, the binding free energy was -16.59 and -18.97 kcal/mol for GRP78-RAB and V-ATPase-DEX, respectively, indicating their stability. According to our findings, RAB and DEX are promising candidates for GRP78 and V-ATPase inhibition experiments, respectively.