The main objective of the present investigation was to analyze, evaluate, and model the behavior in the treatment of real acid mine drainage (AMD) with commercial spiral-wound nanofiltration membranes (NF270 and NF90). Both membranes showed operational differences regarding the effect of pH, temperature, continuous operation, concentration polarization, and fouling. Both NF90 and NF270 presented a high rejection of divalent ions (similar to 100%); however, NF90 showed a greater fouling with AMD. Adjustment of pH in the continuous tests reduced the precipitation of aluminum, and gypsum was identified as the main compound generating a significant decrease in the permeate flow in the membrane. The Spliegler-Kedem model was used to represent rejection and permeate flows, identifying the contribution of convective and diffusive transport in both membranes with a good fit of the model. The results obtained represent important information for a future industrial application to the treatment of AMD by means of commercial NF membranes.