Epoxidation of cottonseed oil by peroxyformic acid (PFA) was studied in a semibatch calorimeter. This liquid–liquid reaction system is composed of different exothermic steps. Thus, a kinetic modeling strategy to diminish the number of parameters to estimate was developed by investigating each reaction system: PFA synthesis and decomposition, ring-opening and epoxidation. A thermal study was conducted by determining heat capacity of the different organic species, and by analyzing the evolution of global heat-transfer coefficient with the reaction extent. The epoxidation reaction was performed in a semibatch reactor under isoperibolic mode within an initial temperature range of 50–70°C, an organic phase of 30–34 wt %, a formic acid molar flow rate of 0.02–0.05 mol/min and an addition time of 25–50 min. The interfacial mass transfer was supposed to be faster than the intrinsic reaction kinetics suppressing the use of mass transfer correlation. Nonlinear regression was used to estimate the kinetic and thermal parameters. The kinetic parameters of epoxidation of the three different fatty acids, namely oleic, linoleic, and its intermediate were estimated. The reaction enthalpy of epoxidation was estimated to −230 ± 3.8 kJ/mol, and the reaction enthalpy of ring-opening was measured to be −90 kJ/mol by Tian–Calvet calorimeter.