Materials exhibiting caloric effects can serve as green alternatives in place of the gas refrigerants used in traditional vapor refrigeration systems, which are facing rising energy usage and environmental issues. This study investigates the barocaloric effect of fatty acids, which are typical phase-change materials. Fatty acids exhibit a reversible isothermal entropy change of about 600 J kg−1 K−1 and an adiabatic temperature change of about 10 K at a pressure less than 60 MPa, resulting from the pressure-driven liquid–solid phase transition. In the solid state, the adiabatic temperature change of fatty acids is larger than that of the n-alkanes with similar transition temperatures. Raman analysis indicates that the population of the distorted molecular chains in fatty acids is remarkably decreased when they are transformed from liquid to solid state, leading to the colossal entropy change. For solid fatty acids, the intermolecular interactions characterized by the hydrogen bonds are significantly strengthened under pressure, which explains their large adiabatic temperature change. This study suggests fatty acids are promising refrigerants for eco-friendly barocaloric cooling.