Hydrothermal liquefaction of sewage sludge to produce bio-oil and hydro-char unavoidably results in the production of high-strength organic wastewater (HTLWW). However, anaerobic digestion (AD) of HTLWW generally has low conversion efficiency due to the presence of complex and refractory organics. The present study showed that granular activated carbon (GAC) promoted the AD of HTLWW in continuous experiments, resulting in the higher methane yield (259 mL/g COD) compared to control experiment (202 mL/g COD). It was found that GAC increased the activities of both aceticlastic and hydrogenotrophic methanogens. The molecular transformation of organics in HTLWW was further analyzed. It was shown GAC promoted the degradation of soluble microbial by-products, fulvic- and humic-like substances as revealed by 3-dimensional fluorescence excitation-emission matrix (3D-EEM) analysis. Gas chromatography mass spectrometry (GC-MS) analysis showed that GAC resulted in the higher degradation of N-heterocyclic compounds, acids and aromatic compounds and less production of new organic species. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) analysis also showed that GAC promoted the degradation of nitrogenous organics. In addition, it was shown that GAC improved the removal of less oxidized, higher nitrogen content, and higher double bond equivalent (DBE) organic compounds. Microbial analysis showed that GAC not only increased the microbial concentration, but also enriched more syntrophic bacteria (e.g., Syntrophorhabdus and Synergistes), which were capable of degrading a wide range of different organics including nitrogenous and aromatic organics. Furthermore, profound effects on the methanogens and the enrichment of Methanothrix instead of Methanosarcina were observed. Overall, the present study revealed the molecular transformation and microbial mechanism in the AD of HTLWW with the presence of GAC.