Hydrothermal liquefaction technology (HTL) is a promising thermochemical method to convert biomass into novel liquid fuels. The introduction of oxides and inorganic acids/bases during the hydrothermal process significantly impacts the yield and composition of bio-oil. However, systematic research on their effects, especially at lower temperatures, remains limited. In this paper, we examine the effects of acidity and alkalinity on cotton stalk hydrothermal bio-oil by introducing homogeneous acids and bases. Given the operational challenges associated with product separation using homogeneous acids and bases, this paper further delves into the influence of heterogeneous oxide catalysts (possessing varying degrees of acidity and alkalinity, as well as distinct microstructures and pore architectures) on the production of cotton stalk hydrothermal bio-oil. The effects of nanoscale oxides (CeO2, TiO2, ZnO, Al2O3, MgO and SiO2) and homogeneous acid–base catalysts (NaOH, K2CO3, Na2CO3, KOH, HCl, H2SO4, HNO3) on the quality of cotton stalk bio-oil under moderate hydrothermal conditions (220 °C, 4 h) were investigated. Characterization techniques including infrared spectroscopy, thermogravimetric analysis, elemental analysis, and GC-MS were employed. The results revealed that CeO2 and NaOH achieved the highest bio-oil yield due to Ce3+/Ce4+ redox reactions, OH-LCC disruption, and ionic swelling effects. Nano-oxides enhanced the formation of compounds like N-ethyl formamide and aliphatic aldehydes while suppressing nitrogen-containing aromatics. The total pore volume and average pore width of oxides negatively correlated with their catalytic efficiency. CeO2 with low pore volume and width exhibited the highest energy recovery. The energy recovery of cotton stalk bio-oil was influenced by both acid and base sites on the oxide surface, with a higher weak base content favoring higher yields and a higher weak acid content inhibiting them. The findings of this research are expected to provide valuable insights into the energy utilization of agricultural solid waste, such as cotton stalks, as well as to inform the design and development of highly efficient catalysts.