For many scientific applications, inverse problems have played a key role in solving important problems by enabling researchers to estimate desired parameters of a system from observed measurements. For example, large-scale inverse problems arise in many global problems and medical imaging problems such as greenhouse gas tracking and computational tomography reconstruction. This dissertation describes advancements in computational tools for solving large-scale inverse problems and for uncertainty quantification. Oftentimes, inverse problems are ill-posed and large-scale. Iterative projection methods have dramatically reduced the computational costs of solving large-scale inverse problems, and regularization methods have been critical in obtaining stable estimations by applying prior information of unknowns via Bayesian inference. However, by combining iterative projection methods and variational regularization methods, hybrid projection approaches, in particular generalized hybrid methods, create a powerful framework that can maximize the benefits of each method. In this dissertation, we describe various advancements and extensions of hybrid projection methods that we developed to address three recent open problems. First, we develop hybrid projection methods that incorporate mixed Gaussian priors, where we seek more sophisticated estimations where the unknowns can be treated as random variables from a mixture of distributions. Second, we describe hybrid projection methods for mean estimation in a hierarchical Bayesian approach. By including more than one prior covariance matrix (e.g., mixed Gaussian priors) or estimating unknowns and hyper-parameters simultaneously (e.g., hierarchical Gaussian priors), we show that better estimations can be obtained. Third, we develop computational tools for a respirometry system that incorporate various regularization methods for both linear and nonlinear respirometry inversions. For the nonlinear systems, blind deconvolution methods are developed and prior knowledge of nonlinear parameters are used to reduce the dimension of the nonlinear systems. Simulated and real-data experiments of the respirometry problems are provided. This dissertation provides advanced tools for computational inversion and uncertainty quantification.