This work presents a CFD–DEM multiphysics co-simulation of continuous stirred-tank reactors (CSTRs) for hydrothermal liquefaction (HTL) of sewage sludge in scale-up study for control strategies. Multiphysics models based on experimental data of HTL process obtained in Parr autoclave engineering systems. The study highlights the strong impact of thermal inertia HTL process for increasing reactor volume, slowing dynamic responses and intensifying temperature gradients. By investigating scales from 0.3 L to 18 L, it was demonstrated that control performance is highly dependent on reactor size: small-scale reactors respond effectively to PID tuning, while large-scale systems require conservative strategies to suppress oscillations caused by high thermal inertia and delayed feedback. Comparative evaluation of PID tuning methods (Ziegler–Nichols, Tyreus–Luyben, Cohen–Coon, Skogestad IMC) confirmed that scale-dependent approaches are critical for ensuring stability and safety. Overall, the integrated CFD–DEM and PID co-simulation framework provides a robust tool for optimizing HTL reactor design, supporting the safe and efficient scale-up of autoclave-based systems toward industrial applications.