Estimating free energy is a fundamental computational challenge, especially in complex biological systems characterised by numerous degrees of freedom. In this study, we investigate the potential of leveraging non-equilibrium free energy estimators within path-based approaches; this offers an appealing feature of inherent parallelism. Building upon our prior work on protein-ligand binding free energy calculations, we develop its non-equilibrium counterpart. We begin by validating our computational strategy on a simple toy model and then extend our analysis to the well-established trypsin-benzamidine complex, serving as a benchmark system. Subsequently, we apply this method to a more intricate, relevant pharmaceutical system to evaluate the performance of our computational pipeline on this complex system. Our results not only demonstrate the feasibility of this approach but also shed light on potential limitations. Furthermore, we showcase the capabilities of the Jarzynski and Crooks estimators employed in our study.