The production of renewable fuels and chemicals is a critical component of global strategies to reduce greenhouse gas emissions. In this regard, pyrolysis oil obtained from biomass comprises hundreds of chemical compounds, thus rendering it a good precursor for manufacturing a variety of fuel products of commercial interest. Despite the large number of contributions describing the products' extraction, upgrading, and potential refining schemes, no bio-oil refinery is currently in operation. The main challenge in building a bio-oil refinery lies in the lack of an economically viable process configuration. Systematic studies comparing alternative refinery concepts, or configurations, are needed to identify the most promising configuration. To the best of our knowledge, this study is the first to use process graph (P-graph) methodology for the synthesis of pyrolysis oil refineries. In particular, this work shows the effectiveness of P-graph methodology in simultaneously calculating the profitability of various biorefinery designs by using data reported in the literature and providing information on how the introduction of new technologies to the database will impact the formation of profitable biorefinery concepts. Our work demonstrates a methodology for the addition of new unit operations to the database generated from the literature. The addition of a centrifuge for water extraction and a wet oxidation system for acetic acid production resulted in the generation of 330 biorefinery configurations, seven of which have a profitability ranging from $1,650 to $23,666/h (USD) with acetic acid and levoglucosan as the main products, respectively. This demonstrates that P-graph methodology is useful for discovering optimum techno-economic scenarios that may otherwise be overlooked.