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Wood-derived bio-oil was investigated as a feedstock for the production of renewable hydrocarbons over commercial hydrotreating CoMoS and NiMoS catalysts. Alumina-supported CoMoS active phase showed better selectivity to diesel-like products than NiMoS phase and higher activity in removal of gaseous intermediates (COx) by hydrogenation. This reaction can play an important role in the reduction of corrosivity at the reactor outlet and determine the process economy. The disadvantage of alumina as a support material was its low stability at high temperatures in presence of water. NiMoS catalyst was found to be more active in decarboxylation and it was possible to reach a steady state production of hydrocarbons having a comparable boiling point distribution with crude oil middle distillates. A test performed with a combination of NiMoS (at the top of the catalyst bed) and CoMoS (at the bottom of the reactor) revealed the key role of the catalyst type and reaction conditions in the first zone of the reactor. The experiments with elevated feeding rates showed the undesirable presence of the not-stabilized reactants behind the first reactor zone. Reaction conditions, catalyst selection and presence of additives (methanol to modify viscosity, DMDS/H2S to stabilize active centers) were combined and optimized to tune the product composition and properties. The catalyst low-temperature activity in the first reactor zone was the limiting factor for the maximum feed rate and reactor capacity. The reaction temperature in this zone strongly affects the boiling point distribution of the product. In case of NiMo catalyst, the reaction temperature above 360 °C in the 3rd zone can reduce molecular weight of the product due to mild cracking. In contrast, temperatures above 400 °C result in fast deactivation preventing thus the establishment of the steady state operating regime.