This study used the Response Surface Methodology (RSM), particularly the Box–Behnken design model, to evaluate the effect of sulfate, alkalinity, and chloramine on iron release from iron pipes historically transporting groundwater, as well as the characteristics of iron corrosion during a changing water quality experiment. The RSM experiment showed that the amounts of Fe3O4, amorphous iron oxide, and intermediate iron products (FeCO3 and Green Rust (GR)) increased in pipe section reactors carrying chloramine-treated water (NH2ClRs), but their α-FeOOH contents decreased and β-FeOOH contents disappeared. In water with high LR (>1.4), the thin and non-protective scale layers containing lower amounts of amorphous iron oxide, Fe(II), derived from newly produced Fe3O4, or FeCO3 or GR could be easily penetrated by oxidants and sulfate ions, resulting in higher iron release. However, the same unstable scale layers did not affect the rates of iron release in water with low LR (≤1.4). The RSM results indicated that there was a close relationship between iron release from these unstable scale layers and water quality (Larson ratio).