Abstract Weaning transition, early nursery environment, and the diet is critical for nursery pig performance and health. Nutritional interventions (i.e., low crude protein diets achieved via decreased SID lysine) and water or in-feed antibiotics are often used to aid in this transition in pig flows prone to endemic enteric pathogens. Therefore, the objective of this study was to investigate the effects of high or low dietary lysine curves, with or without antibiotics, in the first two phases of production on early nursery pig performance. A total of 384 weaned nursery pigs (starting body weight of 5.3 ± 1.6 kg) were randomly assigned to split sex pens (8 pigs/pen) over a 21-day study. Using a 2x2 factorial arrangment, pens were fed one of two dietary treatments over phase 1 (P1) and 2 (P2), with or without antibiotics (n = 12 pens/treatment). The treatments consisted of: 1) low lysine curve (1.15% and 1.2% SID Lys, respectively; LLys); 2) high lysine curve (1.45% and 1.375% SID Lys, respectively; HLys); 3) LLys + antibiotics (LLys+); and 4) HLys + antibiotics (HLys+). During P1, LLys+ and HLys+ received water soluble gentamicin for 5 days, while 50 g/ton Mecadox was added to the LLys+ and HLys+ P2 diets. Four days post-placement, pigs were confirmed positive for Rotavirus and hemolytic E. coli. Individual pig body weights and pen feed disappearance were collected on day 7, 14 and 21 to calculate ADG, ADFI, and G:F. Fecal consistency was scored daily by pen. Data were analyzed with pen as the experimental unit and least squares means reported with the fixed effects of lysine, antibiotics, and their interaction. Regardless of dietary treatment or antibiotic usage, LLys, HLys, LLys+, and HLys+ ADG (0.21, 0.22, 0.20, and 0.21 kg/d, respectively) or ADFI (0.30, 0.28, 0.28, and 0.28 kg/d, respectively) were not different over the 21-day period (P > 0.05). No lysine by antibiotic interactions were reported for any variable measured (P > 0.05). Pig removals and mortalities ranged from 1-4% and did not differ between treatments (P > 0.05). No fixed effects were observed in P1 variables. Although growth rates did not differ, G:F was greater in HLys compared with LLys fed pigs in P2 (0.78 vs. 0.73, P = 0.016) and overall (0.75 vs. 0.69, P = 0.031). Antibiotic usage had no effect on P1, P2, or overall performance parameters. In conclusion, feeding pigs on a high lysine curve or utilizing water soluble and in-feed antibiotics shows minimal benefit to young pigs with a natural enteric pathogen burden.