This study investigates continuous biodiesel production from refined palm oil (RPO) using a 250-cm-length Double-Pipe Static Mixer (DPSM), mixing elements were employed first with the Low-Pressure Drop Static Mixer (LPD-SM) and second with the Kenics Static Mixer (K-SM). Four key independent parameters in the transesterification reaction—methanol (MeOH) to RPO molar ratio, KOH concentration, static mixer length, and residence time—were optimized to achieve the desired methyl ester content (%E, wt.%), set at 96.5 wt.%. From Response Surface Methodology (RSM), The optimal conditions of LPD-SM were MeOH to RPO molar ratio at 5:1, KOH concentration at 0.76 wt.% of RPO, 250 cm static mixer length, and 7.7 min residence time. Conversely, K-SM showed optimal conditions with MeOH to RPO molar ratio at 5.5:1, KOH concentration at 0.81 wt.% of RPO, 250 cm static mixer length, and 7.2 min residence time. Statistical analysis revealed KOH concentration as the most influential parameter, followed by residence time, static mixer length, and MeOH to RPO molar ratio, respectively. In summary, LPD-SM outperformed K-SM in reducing the amount of alcohol and catalyst consumption while maintaining %E at the set point, highlighting its potential as an efficient, sustainable approach for biodiesel production from RPO using a DPSM.