Lactoferrin (Lf) is a glycoprotein present in human and bovine milk with anti-microbial and immune modulating properties. This review aimed to examine the evidence for the effect of Lf supplementation on inflammation, immune function, and respiratory tract infections (RTIs) in humans. Online databases were searched up to December 2020 to identify relevant, English language articles which examined the effect of Lf supplementation in human subjects of all ages, on either inflammation, immune cell populations or activity or the incidence, duration or severity of respiratory illness or RTIs. Twenty-five studies (n = 20 in adults) were included, of which 8/13 studies (61%) in adults reported a decrease in at least one systemic inflammatory biomarker. Immune function improved in 6/8 studies (75%) in adults, with changes in immune cell populations in 2/6 studies (33%), and changes in immune cell activity in 2/5 studies (40%). RTI outcomes reduced in 6/10 studies (60%) (n=5 in adults, n=5 in children), with decreased incidence in 3/9 (33%), and either decreased frequency (2/4, 50%) or duration (3/6, 50%) in 50% of studies. In adults, Lf reduced IL-6 [mean difference (MD): -24.9 pg/mL; 95% CI: -41.64, -8.08 pg/mL], but not C-reactive protein (CRP) [standardized mean difference (SMD): -0.09; 95% CI: -0.82, 0.65], or natural killer (NK) cell cytotoxicity [MD: 4.84%; 95% CI: -3.93, 13.60%]. RTI incidence was reduced in infants and children [odds ratio (OR): 0.78; 95% CI: 0.61, 0.98] but not adults [OR: 1.00; 95% CI: 0.76, 1.32]. Clinical studies on Lf supplementation are limited, though findings show 200mg/day Lf reduces systemic inflammation, while formulas containing 35-833mg/day Lf may reduce RTI incidence in infants and children, suggesting improved immune function. Future research is required to determine optimal supplementation strategies and populations most likely to benefit from Lf supplementation. PROSPERO registration number: CRD42021232186