We redevelop the variational free energy profile (vFEP) method using a cardinal B-spline basis to extend the method for analyzing free energy surfaces (FESs) involving three or more reaction coordinates. We also implemented software for evaluating high-dimensional profiles based on the multistate Bennett acceptance ratio (MBAR) method which constructs an unbiased probability density from global reweighting of the observed samples. The MBAR method takes advantage of a fast algorithm for solving the unbinned weighted histogram (UWHAM)/MBAR equations which replaces the solution of simultaneous equations with a nonlinear optimization of a convex function. We make use of cardinal B-splines and multiquadric radial basis functions to obtain smooth, differentiable MBAR profiles in arbitrary high dimensions. The cardinal B-spline vFEP and MBAR methods are compared using three example systems that examine 1D, 2D, and 3D profiles. Both methods are found to be useful and produce nearly indistinguishable results. The vFEP method is found to be 150 times faster than MBAR when applied to periodic 2D profiles, but the MBAR method is 4.5 times faster than vFEP when evaluating unbounded 3D profiles. In agreement with previous comparisons, we find the vFEP method produces superior FESs when the overlap between umbrella window simulations decreases. Finally, the associative reaction mechanism of hammerhead ribozyme is characterized using 3D, 4D, and 6D profiles, and the higher-dimensional profiles are found to have smaller reaction barriers by as much as 1.5 kcal/mol. The methods presented here have been implemented into the FE-ToolKit software package along with new methods for network-wide free energy analysis in drug discovery.