The phenomenon of pile foundation settlement, especially under weak soil conditions in Can Tho City, has caused many serious failures in civil construction projects. This study focuses on evaluating and comparing the effectiveness of different methods for calculating pile foundation settlement, including analytical methods based on TCVN 10304-2014 and numerical methods using the PLAXIS (FEM). Based on theoretical analysis and practical application at the Phu An Plaza project, the study conducted settlement calculations for various pile group configurations (4, 5, 6, 8, 9, and 16 piles) using both methods. The results showed significant differences in settlement values across each group, with percentage differences of 61.518%, 59.588%, 58.291%, 54.088%, 51.9855%, and 32.222%, respectively. These findings indicate that the discrepancies in settlement and percentage differences are considerably high. The study demonstrates that the FEM-based method (PLAXIS) provides higher accuracy and better reflects the complex geological characteristics of the study area. Therefore, it is recommended as an optimal approach for pile foundation design in weak soil conditions in the Mekong Delta region.