The salinity gradient between seawater and river water has been identified as a promising, clean, renewable, and sustainable energy source that can be converted into electricity using ion-selective membranes in a reverse electrodialysis (RED) configuration. However, the major hindrance to current salinity gradient power (SGP) conversion is its poor energy efficiency due to the use of low-performance membrane processes, which affords power for neither miniaturized devices nor industrial-level applications. Nanofluidics, which combines strong confinement and surface charge effects at the nanoscale, contributes to novel transport properties, including excellent ion selectivity and high ion throughput; thus, nanofluidics may lead to technological breakthroughs and act as an emerging platform for harnessing SGP. Recently, two-dimensional (2D) materials have provided impressive energy extraction performance and further insight into fundamental transport mechanisms and theoretical feasibility. To reach the commercialization benchmark and real-world applications, an array of nanopores and channels that can be scaled up to industrial sizes is in high demand; additionally, it remains challenging to develop macroscale nanofluidic membranes that meet the “selectivity versus throughput” dual requirement. In the first section, we start with our understanding of the underlying mechanism of ion–channel interactions and transport characteristics in nanofluidic channel systems from the microscale to the macroscale. We review our recent efforts in this field by constructing a heterojunction with asymmetric ion transport behavior that generates rectification of the ion flux and creates an osmotic diode, which is composed of two nanofluidic layers with opposite polar charges and different chemical compositions. Another efficient way to improve the performance of the system is introducing charged functional materials intercalated into laminar 2D nanosheets. The intercalated nanofluidic material can be explained by two classical models to account for the synergistic effects that (i) improve the stability and mechanical properties of 2D materials with a fixed interlayer spacing and (ii) provide space charge for modulating ion diffusion; both of these effects contribute to its considerable energy conversion performance. Further, layer-by-layer membranes are superior to traditional membranes consisting of a simple stack because they retain their repulsion effect toward co-ions, largely strengthening the efficiency of ion separation and conversion. In particular, we highlight our views on the role of the 2D phase structure (e.g., semiconductor 2H phase and metallic 1T phase) in which the two phases differ from each other in physical and chemical properties, including ionic conductance, surface charge, and wetting, thereby presenting a state-of-the-art avenue for controlling ion transport. In view of the nature of 2D materials, we also report improved osmotic energy harvesting by exploiting the photoinduced heat gradient and electrons that increase ion mobility and surface charge, respectively. Finally, we point out specific research topics in which a combined project can certainly come into the limelight. For example, we discuss the combination of SGP with desalination systems and water splitting. We expect that this Account will stimulate further efforts toward functionalized 2D nanoporous materials and facilitate interdisciplinary efforts in chemistry, material engineering, environmental science, and nanotechnology.