Down core concentration gradients of dissolved methane and sulfate; isotope gradients of methane, dissolved inorganic carbon, and authigenic carbonate; and organic matter elemental ratios are incorporated into a vent evolution model to describe spatial and temporal variability of sedimentary microbial activity overlying acoustic wipeout zones at Mississippi Canyon (MC) 118, Gulf of Mexico. We tested the hypothesis that these zones indicate areas where sediments are exposed to elevated fluid flux and therefore should contain saturated methane concentrations and enhanced microbial activity from sulfate reduction (SR), anaerobic oxidation of methane (AOM), and methanogenesis (MP). Thirty surficial cores (between 22 and 460 cm deep) were collected from sediments overlying and outside the wipeout zones and analyzed for pore water and solid phase constituents. Outside the wipeout zones, sulfate and methane concentrations were similar to overlying‐water values and did not vary with depth; indicating low microbial activity. Above the wipeouts, nine cores showed moderate activity with gently sloping sulfate and methane concentration gradients, methane concentrations <20 μM, and isotope depth gradients indicative of organic matter oxidation. In stark contrast to this moderate activity, four cores showed high microbial activity where sulfate concentrations were depleted by ∼50 cm below seafloor, maximum methane concentrations in the decompressed cores were above 4 mM, and down core profiles of δ¹³C‐CH₄ and δ¹³C‐dissolved inorganic carbon (DIC) indicated distinct depth zones of SR, AOM, and MP. Bulk organic matter analysis suggested that the high activity was supported by an organic source that was enriched in carbon (C:N ∼15) and depleted in δ¹⁵N and δ¹³C compared to other activity groups, possibly due to the influx of petroleum or chemosynthetically fixed carbon. Within high activity cores, the δ¹³C‐DIC values were similar to the δ¹³C‐CaCO₃ values, a result expected for authigenic carbonate recently precipitated. However, these values were dissimilar in moderate activity cores, suggesting that microbial activity was higher in the past. This study provides evidence that the fluid flux at MC 118 varies over time and that the microbial activity responds to such variability. It also suggests that sediments overlying wipeout zones are not always saturated with respect to methane, which has implications for the formation and detection of gas hydrate.