This study focuses on the development of a time-variable regional geo-potential model for Antarctica using the spherical cap harmonic analysis (SCHA) basis functions. The model is derived from line-of-sight gravity difference (LGD) measurements obtained from the GRACE-Follow-On (GFO) mission. The solution of a Laplace equation for the boundary values over a spherical cap is used to expand the geo-potential coefficients in terms of Legendre functions with a real degree and integer order suitable for regional modelling, which is used to constrain the geo-potential coefficients using LGD measurements. To validate the performance of the SCHA, it is first utilized with LGD data derived from a L2 JPL (Level 2 product of the Jet Propulsion Laboratory). The obtained LGD data are used to compute the local geo-potential model up to Kmax = 20, corresponding to the SH degree and order up to 60. The comparison of the radial gravity on the Earth’s surface map across Antarctica with the corresponding radial gravity components of the L2 JPL is carried out using local geo-potential coefficients. The results of this comparison provide evidence that these basis functions for Kmax = 20 are valid across the entirety of Antarctica. Subsequently, the analysis proceeds using LGD data obtained from the Level 1B product of GFO by transforming these LGD data into the SCHA coordinate system and applying them to constrain the SCHA harmonic coefficients up to Kmax = 20. In this case, several independent LGD profiles along the trajectories of the satellites are devised to verify the accuracy of the local model. These LGD profiles are not employed in the inverse problem of determining harmonic coefficients. The results indicate that using regional harmonic basis functions, specifically spherical cap harmonic analysis (SCHA) functions, leads to a close estimation of LGD compared to the L2 JPL. The regional harmonic basis function exhibits a root mean square error (RMSE) of 3.71 × 10−4 mGal. This represents a substantial improvement over the RMSE of the L2 JPL, which is 6.36 × 10−4 mGal. Thus, it can be concluded that the use of local geo-potential coefficients obtained from SCHA is a reliable method for extracting nearly the full gravitational signal within a spherical cap region, after validation of this method. The SCHA model provides significant realistic information as it addresses the mass gain and loss across various regions in Antarctica.