Neonatal calf diarrhea remains the most common cause of mortality and antimicrobial use in dairy calves. Reduced overall antimicrobial use necessitates research on viable alternative therapies for calf diarrhea. Lactoferrin, an iron-binding protein found in colostrum, has been shown to improve growth and reduce mortality in pre-weaned heifer calves. The objective of this study was to investigate the effect of lactoferrin on the health of pre-weaned dairy heifer calves with diarrhea. This randomized controlled field trial was conducted on 5 commercial dairy farms in Ohio. In total, 485 calves (≤21 d of age) were enrolled after first diagnosis of diarrhea (fecal score ≥3 defined as loose to watery), and randomly assigned to receive an oral dose of lactoferrin (3 g lactoferrin powder dissolved in 30 mL water) or water (control) once daily for 3 consecutive days. Health assessments were conducted on the day of enrollment and 1, 2, 3, 7, 14, 21, 28, and 35 d post-enrollment. A poisson regression model was used to test differences between treatments in frequency of disease through 35 d post-enrollment. Median calf age at enrollment was 11 d, and ranged from 1 to 21 d of age. On the day of enrollment, 51.3% (123/240) and 52.2% (128/245) of calves in the control and lactoferrin treatment groups, respectively, were diagnosed with severe diarrhea (fecal score = 4). The frequency of diarrhea through 35 d post-enrollment did not differ between control and lactoferrin treatment groups (RR: 1.01, 95% CI: 0.93–1.08; P = 0.87). Further, depression (depression score ≥2 defined as moderate to severe depression) was not different for calves supplemented with lactoferrin compared with calves in the control group (RR: 0.85, 95% CI: 0.59–1.22; P = 0.37). This study suggests supplementing lactoferrin to dairy calves with diarrhea does not influence the frequency of diarrhea or depression 5 wk post-diagnosis; however, additional analyses of secondary outcomes and future research may uncover longer-term benefits of supplemental lactoferrin on morbidity and mortality in dairy heifer calves.