Changes in the terrestrial total water storage (TWS) have been estimated at both global and river basin scales from the Gravity Recovery and Climate Experiment (GRACE) mission and are still being detected from its GRACE Follow-On (GRACE-FO) mission. In this contribution, the sixth release of GRACE-FO (RL06) level-2 products applying DDK5 (decorrelation filter) were used to detect water mass variations for the Nile River Basin (NRB) in Africa and the Mega Aquifer System (MAS) in Asia. The following approach was implemented to detect the mass variation over the NRB and MAS: (1) TWS mass (June 2018–June 2021) was estimated by converting the spherical harmonic coefficients from the decorrelation filter DDK 5 of the GRACE-FO Level-2 RL06 products into equivalent water heights, where the TWS had been re-produced after removing the mean temporal signal (2) Precipitation data from Global Precipitation Climatology Project was used to investigate the pattern of change over the study area. Our findings include: (1) during the GRACEFO period, the mass variations extracted from the RL06-DDK5 solutions from the three official centers—CSR, JPL, and GFZ—were found to be consistent with each other, (2) The NRB showed substantial temporal TWS variations, given a basin average of about 6 cm in 2019 and about 12 cm in 2020 between September and November and a lower basin average of about −9 cm in 2019 and −6 cm in 2020 in the wet seasons between March and May, while mass variations for the MAS had a relatively weaker temporal TWS magnitude, (3) the observed seasonal signal over the NRB was attributed to the high intensity of the precipitation events over the NRB (AAP: 1000–1800 mm yr−1), whereas the lack of the seasonal TWS signal over the MAS was due to the low intensity of the precipitation events over the MAS (AAP:180–500 mm yr−1).