Cleavage of strong C-O bonds without breaking C-C/C-H bonds is a key step for catalytic conversion of renewable biomass to hydrocarbon feedstocks. Herein we report multistep sequential engineering of orthogonal Lewis acid and palladium nanoparticle (NP) catalysts in a metal-organic framework (MOF) built from (Al-OH) n secondary building units and a mixture of 2,2'-bipyridine-5,5'-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands (1) for tandem C-O bond cleavage. Ozonolysis of 1 selectively removed pdac ligands to generate Al-2(OH)(OH2) sites, which were subsequently triflated with trimethylsilyl triflate to afford strongly Lewis acidic sites for dehydroalkoxylation. Coordination of Pd(MeCN)(2)Cl-2 to dcbpy ligands followed by in situ reduction produced orthogonal Pd NP sites in 1-OTf-PdNP as the hydrogenation catalyst. The selective and precise transformation of 1 into 1-OTf-PdNP was characterized step by step using powder Xray diffraction, transmission electron microscopy, thermogravimetric analysis, inductively coupled plasma mass spectrometry, infrared spectroscopy, and X-ray absorption spectroscopy. The hierarchical incorporation of orthogonal Lewis acid and Pd NP active sites endowed 1-OTf-PdNP with outstanding catalytic performance in apparent hydrogenolysis of etheric, alcoholic, and esteric C-O bonds to generate saturated alkanes via a tandem dehydroalkoxylation-hydrogenation process under relatively mild conditions. The reactivity of C-O bonds followed the trend of tertiary carbon > secondary carbon > primary carbon. Control experiments demonstrated the heterogeneous nature and recyclability of 1-OTf-PdNP and its superior catalytic activity over the homogeneous counterparts. Sequential engineering of multiple catalytic sites in MOFs thus presents a unique opportunity to address outstanding challenges in sustainable catalysis.