Methane constitutes one of the largest carbon reservoirs in the Earth system and plays a pivotal role in regulating global climate. Variations in atmospheric and oceanic methane concentrations have been proposed as major triggers of numerous global environmental perturbations throughout Earth’s history. Accurately assessing the role of methane in the global carbon cycle and climate change therefore requires intensified observations and investigations of methane seepage in modern oceans, particularly the establishment of robust geochemical fingerprints for identifying and reconstructing submarine methane seepage. Nickel (Ni) serves as a key metal cofactor in metalloenzymes involved in both methane production and consumption, and its isotope fractionation has considerable potential as a tracer of microbial methane metabolism. This study focuses on the early diagenetic cycling of Ni in sediments from the active Haima cold-seep field on the northern continental slope of the South China Sea. Sediment and pore-water samples collected from representative sites characterized by contrasting methane-seepage intensities have been systematically analyzed for their elemental and isotopic geochemical compositions. By employing Ni-C-S multi-isotopes in combination with a one-dimensional reaction-transport model, our study constrained the migration and transformation pathways of Ni, as well as its isotopic fractionation behavior, across different cold seep environments. It further elucidated the mechanisms governing the Ni isotopic response to methane seepage and microbially mediated anaerobic oxidation of methane (AOM). The results are expected to establish Ni isotopes as a novel geochemical proxy for the dynamic assessment of natural gas hydrate systems and the reconstruction of ancient methane-release events.