Hydrothermal liquefaction (HTL) has remarkable potential for efficient conversion of abundant, decentralized organic wastes into renewable fuels. Because waste is a highly distributed resource with context-dependent economic viability, selection of optimal deployment sites is slowed by the need to develop detailed techno-economic analyses (TEA) for the thousands of potential deployment locations, each with their own unique combinates of scale, proximity to infrastructure/markets, and feedstock properties. An economic modeling framework that requires only easily obtainable inputs for assessing economic performance would therefore allow multiplexed analysis of many thousands of cases, whereas traditional TEA would not be possible for more than a handful of cases. Within such a context, the present study uses machine learning to guide development of a TEA and modeling framework which provides accurate cost predictions using three key inputs – feedstock cost, biocrude yield, and process scale – to estimate the minimum fuel selling price (MFSP) that an HTL process can achieve. The structure of the proposed framework is informed and based on empirical observations of cost projections made by a detailed TEA over a wide range of feedstock costs, biocrude yields, and process scales. A machine learning guided process was used to identify, train, and test a series of models using auto-generated data for training and independently reported data for testing. The most accurate model consists of three terms and requires 6 adjustable parameters to predict independently published values of MFSP (N = 28) to within an average value of ± 20.4%. It is demonstrated that the reduced-order model’s predictions fall within 40% of the corresponding published values 95% of the time, and in the worst case, the associated discrepancy is 45.9%, suggesting that the accuracy of the machine learned model is indeed comparable to the TEAs that were used to build it. Moreover, the terms in the model are physically interpretable, conferring greater reliability to the use of its predictions. The model can be used to predict the dependence of MSFP on biocrude yield, scale, and feedstock cost; interestingly, MFSP is insensitive to biocrude yield and/or scale under many situations of interest and identifying the critical value for a given application is crucial to optimizing economic performance. The proposed model can be also extended to evaluate economic performance of newly developed HTL-based processes, including catalytic HTL, and the methodological framework used in this study is deemed appropriate for the development of machine learned TEA models in cases of other similar waste-to-energy technologies.