Tetracycline antibiotic wastewater with high chemical oxygen demand (COD) concentration and containing biorefractory compounds was investigated in a lab-scale up-flow anaerobic sludge blanket (UASB) and anoxic-oxic (A/O) reactor. Specific methanogenic activity (SMA) was determined to reveal the inhibition levels of methane production and volatile fatty acid (VFA) accumulation. The results showed that microorganisms can adapt to tetracycline or oxytetracycline when the concentration of antibiotics is less than 400 mg/L. Acetic acid, propanoic acid, and n-butyric acid accounted for more than 90% of VFA with increasing antibiotic concentration from 50 mg/L to 600 mg/L. During the 215 days of operation, the concentration of tetracycline antibiotic increased from 0 to 95 mg/L, and the COD concentration from 3500 to 6,500 mg/L. The average COD and tetracycline antibiotic removal rates of the reactors were maintained above 90%. The methane production of the UASB reactor achieved 0.32 L/g COD. VFA accumulation was observed when tetracycline antibiotic concentration increased to 47.5 mg/L. The sludge granule diameter increased from 0-300 μm to 300-1,500 μm during the operation. Rod-shaped and coccus-shaped organisms with pores and internal channels on the granule surface were observed using scanning electron microscopy. In the internal space, methanogenic filamentous bacteria constitute a rock-steady structure.