In ruminants, colostrum is the main source of immunoglobulins for the newborn animal, conferring immune protection until the immune system becomes active and able to synthesize its own immunoglobulins. Serotonin (5-HT), a biogenic amine derived from tryptophan, has stimulatory effects on many physiological processes, including components of the innate (mastocytes, eosinophils, and natural killer cells) and adaptive (T and B lymphocytes) immune systems. Based on the known effects of 5-HT on the immune system, we hypothesized that increased concentrations of 5-HT, through administration of its precursor 5-hydroxy-l-tryptophan (5-HTP), may positively affect development of the calf's immune system and therefore support health and growth performance during the first weeks of life. Eighteen calves were randomly assigned to 1 of 2 experimental groups (control and 5-HTP), resulting in n = 9 per treatment group. Both groups received 2 colostrum meals from a common pool of colostrum. Thereafter, calves were fed milk replacer twice daily for 30 d. In the 5-HTP group, colostrum and milk replacer were supplemented with 1.5 mg of 5-HTP/kg of birth weight during the first 15 d after birth. Body weight was recorded at birth and on d 5, 10, 15, and 30 after birth. Blood samples were collected every morning (0800 h) before feeding from birth until d 5 and then on d 7, 9, 11, 13, 15, and 30 after birth. Serum 5-HT concentrations were increased as a consequence of the 5-HTP supplementation. Plasma immunoglobulin G concentrations did not differ between groups throughout the experimental period. The blood mRNA abundance of several factors related to the innate and adaptive immune system [nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), serum amyloid A-1 (SAA1), chemokine C-C motif ligand 5 (CCL5), cyclooxygenase 2 (PTGS2), haptoglobin (HP), and IL-1β] were increased in calves supplemented with 5-HTP. Supplementation of 5-HTP did not affect any of the measured metabolites (fatty acids and glucose) or minerals (calcium and magnesium) or milk feed intake, feed conversion ratio, and growth. In conclusion, 5-HTP supplementation induced an increase of 5-HT concentrations in blood and caused an increase in mRNA abundance of several factors related to the innate and adaptive immune systems, which might increase the protection of the calf against external agents.