Cancer patients receiving chemotherapy often experience metallic taste and immunity dysfunction, which negatively impacts their nutritional status. However, there has been no effective treatment for this frequent side-effect. In this study, dietary supplementation through lactoferrin (LF) was developed as a treatment to reduce metallic taste disorder and improve immune system for cancer patients. Sixteen patients with self-reported metallic taste disorder since undergoing chemotherapy and 10 healthy subjects were recruited in this study. All participants took LF supplements, 3 tablets per day (250 mg/tablet), for 30 d. Saliva samples were collected at baseline, 30 d after LF supplements daily intake, and 30 d after LF supplementation ended. Taste function of cancer patients was assessed by a self-perceived taste abnormality questionnaire. Salivary proteome and minerals were analyzed at each time point of LF supplementation. LF supplementation for 30 d significantly decreased (P < 0.05) taste abnormality score and salivary Fe in cancer patients. Production of metallic taste was related with the loss of salivary immune proteins. LF supplementation led to an overall increase of immune defense proteins in saliva of all human subjects, including α-amylase, zn-α-2-GP, prolactin-inducible protein (PIP), and low-abundance proteins (pH 5.5–8.5, MW 25–75 kDa) such as immunoglobulin heavy chain, annexin A1, carbonic anhydrase VI precursor (CAVI), proteinase inhibitor, and α-amylase. For 60% of cancer patients, a post-LF supplementation effect further increased the intensity of α-amylase. LF treatment effectively reduced metallic taste disorder induced by chemotherapy and increased production of salivary defense proteins in human subjects.