Health and performance of pre-weaned dairy calves have great influence on adult life performance. Among the diseases that affect young dairy calves, diarrhea and pneumonia are the most prevalent and economically important. This study evaluated the effects of a non-specific immune stimulant (IS; Amplimune, NovaVive Inc., Canada) on the health of Jersey and Jersey-cross heifer calves within their first month of life. We hypothesized that calves receiving IS would have lower weekly health scores (HS) and decreased disease treatment hazard. Newborn heifer calves (5 ± 2d) in a large well-managed dairy were randomly allocated to receive either 1mL of saline (CON; n = 458) or 1mL of IS (BTIS; n = 449) at nursery before transport to grower (~18h from Minnesota to New Mexico), or 1mL of IS immediately after transport to grower (ATIS; n = 453). All treatments were administered subcutaneously and blood samples were collected for analysis of serum total solids. Calves were health scored weekly based on nasal/ocular discharge, coughing, ear position, temperature, attitude and fecal consistency. Interval to disease treatment was analyzed using Cox proportional hazards regression and HS by logistic regression. For all analysis, CON was set as reference and non-significant variables were removed from the models using backward stepwise elimination. The number of disease treatment events was lower than the national average. A total of 155 calves were treated at least once and 14 calves died within the first month of life. The proportion of calves treated for any disease was 9.8, 11.2 and 13.1%; whereas mortality was 1.1, 1.6 and 2.4% for BTIS, ATIS and CON groups, respectively. Weekly HS did not differ between BTIS and ATIS calves versus CON calves. Calves that received IS before transport had reduced hazard of treatment for pneumonia when compared with CON (HR: 0.54; 95% CI: 0.31–0.94; P = 0.03). In conclusion, the administration of IS did not influence weekly HS but IS administration before transport reduced the number of calves treated for pneumonia within the first 30 d of life.