This work evaluates the sustainability of small-scale biorefineries as a potential enterprise alternative to be introduced in rural areas based on experimental and simulation data. Four scenarios were evaluated: the first scenario involves the production of guacamole, the second involves the production of animal feed, and the third and fourth scenarios involve the extraction of bioactive compounds and the production of avocado oil or animal feed, respectively. In addition, all scenarios produce biogas and fertilizer. Each of the scenarios were evaluated considering the technical, economic, environmental, and social aspects. As a main result, the first scenario showed the lowest operating and investment costs, as well as the lowest economic profitability (profit margin 35%). On the other hand, the third and fourth scenarios present the highest investment and operating expenses (OpEx USD 6.2 million per year and CapEx USD 1.0 million), but their profit margins are in the 60–70% range. Furthermore, a life-cycle assessment (LCA) was carried out and allows inferring that the transformer link presents the highest environmental impact of the entire value chain and that the carbon footprint for all scenarios ranges between 1.01–2.41 kg CO2 eq per kg avocado. Similarly, the social impact methodology shows that the proposed scenarios do not present any social risk. Thus, the biorefinery for animal feed, bioactive compounds, biogas, and fertilizer was selected as the best option to be implemented in Caldas.