Nanopore-based devices have provided exciting opportunities to develop affordable label-free DNA sequencing platforms. Over a decade ago, graphene has been proposed as a two-dimensional (2D) nanopore membrane in order to achieve single-base resolution. However, it was experimentally revealed that clogging of the graphene nanopore can occur due to the hydrophobic nature of graphene, thus hindering the translocation of DNA. To overcome this problem, the exploration of alternative 2D materials has gained considerable interest over the last decade. Here we show that a Ti₂C-based MXene nanopore functionalized by hydroxyl groups (–OH) exhibits transverse conductance properties that allow for the distinction between all four naturally occurring DNA bases. We have used a combination of density functional theory and non-equilibrium Green’s function method to sample over multiple orientations of the nucleotides in the nanopore, as generated from molecular dynamics simulations. The conductance variation resulting from sweeping an applied gate voltage demonstrates that the Ti₂C-based MXene nanopore possesses high potential to rapidly and reliably sequence DNA. Our findings open the door to further theoretical and experimental explorations of MXene nanopores as a promising 2D material for nanopore-based DNA sensing.