1,2,4,5-Tetramethylbenzene (durene) is a value-added aromatic used in producing high-end polyesters. The known synthesis routes of durene by 1,2,4-trimethylbenzene (1,2,4-TriMB) methylation with methanol or direct conversion from syngas suffer from low alkylation efficiency and diverse product distribution. Here, we show a novel pathway to synthesize durene by coupling 1,2,4-TriMB methylation with syngas conversion over a bifunctional catalyst ZnZrO_x–HZSM-5 (ZZO–Z5). Over 90% durene selectivity in tetramethylbenzene and 56.5% tetramethylbenzene selectivity in hydrocarbons with 21.3% 1,2,4-TriMB conversion were obtained at 320 °C and 3.0 MPa. Upon further doping of 5 wt% Cu into ZZO, the resultant 5CuZZO–Z5 gave comparable 1,2,4-TriMB conversion (21.2%) compared with ZZO–Z5 at 290 °C. When syngas was used as a methylation reagent instead of methanol, the methylation rather than the disproportionation of 1,2,4-TriMB was the main process for durene production and the durene selectivity improved significantly. Results revealed that the synergistic interaction within CuZnZr ternary solid solution was necessary to advance the catalytic activity and stability. The introduction of Cu reduced the apparent activation energy but increased the adsorption of CO and the formation of intermediate CH_xO* (x = 1–3). The mechanism involved CO hydrogenation on 5CuZZO to generate the reactive methylation species CH_xO*, which migrated to the Z5 pore for 1,2,4-TriMB methylation to form durene. The two bifunctional catalysts ZZO–Z5 and 5CuZZO–Z5 exhibited excellent stability within 100 h.