This study investigated the long-term effects of high inclusion of reduced-fat corn distillers grains with solubles (RFDG) with and without monensin on intake, production, milk fatty acid profile, and plasma AA profile in lactating cows. The experiment was conducted for 11 wk (2-wk diet adaptation, 9-wk experimental period of data collection) with 36 Holstein cows (80 ± 31 DIM; mean ± SD at start of trial) in a randomized block design. Cows were blocked by parity and DIM and assigned to the following diets: (1) CON, control diet; (2) DG, CON with RFDG included at 28.8% (dry matter basis) replacing soybean meal, soyhulls, and supplemental fat; (3) DGMon, DG with monensin (Rumensin; Elanco Animal Health, Greenfield, IN) supplemented at a rate of 20 mg/kg of DM. Data were analyzed with a model that included the fixed effect of treatment, week, and interaction of diet and week, the random effect of cow within block, repeated measurements were included. Orthogonal contrasts were used to compare CON vs. DG and DGMon and DG vs. DGMon. Milk yield was not affected (40.3 vs. 40.8 kg/d; P = 0.58) by DG and DGMon compared with CON. However, dry matter intake (DMI; 24.9 vs. 26.4 kg/d), milk fat yield (1.12 vs. 1.55 kg/d), milk protein yield (1.24 vs. 1.32 kg/d), and energy-corrected milk yield (37.7 vs. 43.5 kg/d) decreased (P < 0.01) for DG and DGMon compared with CON. Feeding DGMon compared with DG did not affect (P ≥ 0.102) DMI (24.4 vs. 25.4 kg/d) and milk yield (39.2 vs. 41.3 kg/d), but decreased (P ≤ 0.02) milk fat yield (1.08 vs. 1.23 kg/d), milk protein yield (1.20 vs. 1.28 kg/d), and energy-corrected milk yield (36.0 vs. 39.4 kg/d). Interactions between treatment and wk (P ≤ 0.08) for DMI, milk fat yield, and energy-corrected milk indicate production responses to DG and DGMon vs. CON were decreased over the experimental period. In the current study, feeding a high-DG diet did not sustain long-term DMI and production, and supplementing monensin to a high-DG diet further decreased DMI and production.