In this study, the reliability differences between a normal structure and a six-sided protective structure are investigated for 300 mm fan-out wafer-level packaging. Theoretical analysis indicates that the six-sided protective structure exhibits lower thermal stress (dropping by 9.06%) and superior thermal stability. The introduced epoxy molding compound (EMC) protective layer bonds tightly with other layers without changing the performance of the solder balls, such as shear strength and failure modes. After reliability testing, all the normal structure samples passed the high accelerated stress test (HAST) and temperature cycling testing (TCT), but none passed the pressure cooking testing (PCT). By contrast, the six-sided protective structure samples passed all tests. Scanning acoustic microscopy and cross-sectional scanning electron microscopy (SEM) pictures further confirmed that the six-sided protective structure passed the PCT. This result indicates that the reliability of the six-sided protective structure has been strengthened, consistent with the simulation analysis. A packaging solution for enhancing reliability by reducing structural thermal stress has been suggested.