Acid mine drainage and mining wastewaters contain, depending on the source, elevated concentrations of metals, e.g. nickel (Ni2+), and oxyanions, e.g. selenate (SeO42-) and sulfate (SO42-). This study compared the performance of two reactor configurations, a biotrickling filter (BTF) and an upflow anaerobic sludge blanket (UASB) reactor, for the treatment of model mining wastewater contaminated with SeO42-, SO42- and Ni2+. The Se removal efficiency of the BTF biofilm was improved by >70% in the presence of SO42-. In contrast, the Se removal performance of the UASB reactor was not affected by the presence of SO42-. The addition of Ni2+ decreased the oxyanion (SO42- and SeO42-) removal efficiency of both the BTF and UASB reactor by >30%. However, the UASB reactor recovered more quickly (similar to 10 days after Ni2+ addition) from Ni2+ toxicity as compared to the BTF (similar to 22 days after Ni2+ addition). A Ni2+ removal efficiency of more than 80% was achieved for both the BTF and UASB reactor. Ni2+ was mainly removed via sulfidic (HS-) precipitation by forming nickel sulfide (Ni3S4). Scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM-EDX) and powder X-ray energy diffraction (P-XRD) revealed entrapped Se and selenium monosulfide (SeS) in the biofilm and granules of both reactor configurations, which could be potentially recovered for further reuse applications. This study demonstrated that the feed wastewater characteristics and the reactor configuration are key factors in achieving an efficient treatment of Se-laden mine drainage wastewater.