Proterozoic rocks of the Isa superbasin in northern Australia host globally significant Pb-Zn-Ag deposits as well as a series of Cu, Cu-Au, and U deposits. This numerical modeling study explores fluid-flow patterns during the shortening deformation event associated with the initial stages of the structural inversion of the Isa superbasin at ca. 1575 Ma. The major objective of this work is to explore a series of scenarios for the Isa superbasin. The models of coupled deformation and fluid-flow processes presented in this paper include (1) basin fluid flow in a basin-inversion environment subject to shortening, (2) syntectonic dehydration-related fluid production, (3) hydrofracturing and permeability creation, (4) aquifer permeability changes with depth, and (5) the effect of a buried fault versus an open fault. In a scenario only considering the interaction of deformation and fluid flow during basin inversion, intense upward flow along basin-scale faults and strong lateral flow along the well-connected segments of major aquifer horizons dominate the fluid-flow field. The combinations of deformation features, aquifer geometry, and fault distribution result in different fluid-flow patterns across the simulated section. This seems to suggest some fluid compartmentalization, resulting in variations in fluid chemistry and mineralization across the region. The incorporation of dehydration fluid production and hydrofracturing-permeability creation both significantly increase fluid flow, expressed as greater fluid fluxes and volumes along faults and aquifer units. Scenarios that consider hydrofracturing-permeability development also indicate more efficient fluid migration during basin inversion. Permeability creation as a result of hydrofracturing allows fluids to migrate more efficiently through rocks along newly developed high-permeability horizons and to converge more efficiently into basin-scale faults. Assuming an open fault (i.e., a fault with access to the surface) also increases upward fluid flux along the fault. The models also demonstrate the effects of changing permeability of aquifer units with depth on fluid flow. The key implication of the current modeling results is that shortening deformation during the inversion of the Isa superbasin, assisted by dehydration-related fluid release at deep levels and hydrofracturing-related permeability generation, could have created efficient multiple fluid pathways through the stratigraphic sequence with multiple aquitard units and increased fluid flow along and near faults in the region.