The lowermost Mississippi River (LMR) is important to the environment and economy of continental United States. Although bathymetric data have been collected over many decades at numerous cross-sectional sounding points, there has been no consensus on appropriate interpolator for generating bathymetry. Such interpolation is critical to reliable assessments of channel morphology and channel change, which serve for dredging, engineering projects, and mapping of navigation hazards. This study aimed to identify an optimal spatial interpolation for mapping the river bathymetry from cross-sectional sounding measurements. We evaluated a variety of spatial interpolation methods including Inverse Distance Weighting (IDW), Ordinary Kriging (OK), Radial Basis Function (RBF), and Local Polynomial Interpolation (LPI). In addition, we also considered the anisotropic form of IDW (Elliptical IDW as EIDW), that of OK (OKA), and Universal Kriging (UK). Two reaches in the LMR, located between approximately RM (River Miles) 170-140 and RM 60-35, were chosen as the study area. Those interpolators were compared in terms of root-mean-square error (RMSE), mean absolute error (MAE), bias, and coefficient of determination (r 2). Our results demonstrate that both of RBF and OKA performed the best in mapping the bathymetry of study reaches. Furthermore, our results also indicate that the addition of anisotropy can significantly reduce RMSE by 5-20%, as compared to isotropic methods. The findings better inform other researchers on selecting a proper interpolation technique for mapping river bathymetry, particularly for other reaches of the Mississippi River.