Identification of inherently safer and intensified reaction conditions is a vital step for transformation of traditional batch/semibatch synthesis to continuous operation. Accelerating reactions is challenged by several safety and efficiency issues including thermal runaway risk, side reactions, final product degradation, and reactor overpressure. This work demonstrates the use of response surface methodology to identify inherently safer and more efficient intensified reaction conditions for 3-methylpyridine N-oxidation performed in a semibatch pressure-resistant isothermal calorimeter. The experimental conditions were selected to screen various operating-variable combinations using Box–Behnken design of experiments. Regression models were developed correlating the catalyst amount, oxidizer dosing-rate, and reaction temperature with reactor pressure and N-oxide yield; good agreement with experimental data obtained in the present study and from literature was achieved. Results indicate that, even when conducted in a semibatch mode, the reaction is inherently safer and more efficient under intensified conditions.