This study aimed to evaluate lytic bacteriophage supplementation in pre-weaned dairy calves on disease occurrence, performance, and biochemical parameters. Two hundred Holstein × Gyr crossbred female calves were divided into two groups: CON, no supplementation; and PHAGE, bacteriophage supplementation (1 g·d⁻¹) from day 3 until day 70 of life. Calves were monitored daily for age of first diarrheal episode and its duration. Fecal samples were cultured for bacterial isolation and PCR was performed to identify Escherichia coli virulence genes and to confirm Salmonella spp. Performance outcomes were evaluated up to 80 d of age. Blood samples were collected to determine serum levels of total proteins, albumin, cholesterol, γ-glutamyl transferase, and urea. PHAGE group had fewer days with diarrhea (PHAGE: 4.68 d, CON: 6.61 d; P = 0.03). Fecal samples of three animals in PHAGE and nine in CON were positive for E. coli after PCR tests. Average daily gain of PHAGE was higher up to 80 d of life (P < 0.05). PHAGE mean was lower for albumin and higher for urea (P = 0.004 and P < 0.001, respectively). Phage therapy during the pre-weaned period reduced the duration of neonatal diarrhea, providing greater weight gain for calves.