Anaerobically-pretreated cardboard wastewater (APCW) contains significant residuals of organics, nitrogen species and coarse suspended solids, making the effluent quality not complying for disposal. This is the 1st investigation for treating APCW by an auto-aerated immobilized biomass (AIB) reactor packed with sponge media and ventilated naturally. The optimum hydraulic retention time (HRT) was 4.3 h, achieving CODtotal, CODsoluble, TSS, VSS, TKN, carbohydratetotal, and carbohydratesoluble removal efficiencies of 63.0, 58.8, 71.6, 66.0, 25.5, 38.0, and 33.5%, respectively. The bronopol (2-bromo-2-nitropropan-1,3-diol) supplementation to the APCW feed reduced those removal efficiencies by 20%–40%. The mitigation of bronopol toxicity was illustrated regarding the secretion of extracellular polymeric substances (EPS) to protect the bacterial biomass against the severe environment. The FTIR bands revealed the presence of bound EPS at 1633 and 1403 cm−1 and free EPS at 1035 and 862 cm−1. The alkanes (CH) peaks could be an indicator for the biodegradation of bronopol into formaldehyde by the sponge-retained biomass. An artificial neural network (ANN) model was developed and optimized to predict the COD removal efficiency based on the reactor’s operational conditions, attaining high accuracy (R2: 0.90). The model findings verify the applicability of ANN to simulate the performance of sponge-packing systems, retaining various aerobic, anoxic, and anaerobic species.