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Simple Summary: Over the years, the poultry industry has relied on the use of in-feed antibiotics as a growth-promoting agent and for the prevention of diseases. However, antibiotic use has brought about pathogens that are resistant to antimicrobials. To this end, spray-dried plasma (SDP), an animal blood by-product that is rich in protein-containing lipids, peptides, immunoglobulins, transferrin, and fibrinogen, is being explored as a replacement for in-feed antibiotics in poultry. We evaluated the immunological and biochemical profile of SDP in order to understand how it enhanced performance values when supplemented to a broiler diet. At the end of the four-week study, our findings demonstrated a decrease in the number of heterophils and an increase in immunoglobulin in circulation, with oxidative stress falling in the normal range. Bifidobacteria counts also increased in the SDP-supplemented treatment. This demonstrated that SDP supplementation prevented infection and caused an increase in immunoglobulin concentration required to support intestinal development and gut microbiota modulation. Spray-dried plasma (SDP) contain a variety of functional proteins that play an immunomodulatory role. To evaluate the potential of SDP to stimulate the immune system, day-old Ross 708 male broiler chicks (200) were allocated randomly to five dietary treatments. Treatment 1 (CX) comprised chicks fed basal unmedicated corn–soybean meal (SBM) without the addition of SDP. Treatment 2 (MX) includes chicks fed unmedicated corn–SBM basal containing Bacitracin methylene disalicylate (BMD) at 0.055 g/kg diet. Treatments 3 (SDP1), 4 (SDP2), and 5 (SDP3) contained chicks given unmedicated corn–SBM basal, into which SDP was included at 10, 20, and 30 g/kg diet, respectively. On d 7, 14, and 21, chicks' body weight and FCR were calculated. Additionally, leucocyte counts, oxidative status, and IgY concentrations were determined in blood. On d 23, fecal populations of selected indicator bacteria species were determined. Results showed that FCR for SP3 was superior (p < 0.05) to other treatments. Likewise, heterophil numbers decreased in MX and SDP treatments compared to CX. Circulating IgY concentration was higher for SDP dietary treatments (p < 0.05) compared to MX. In conclusion, dietary SDP at 30 g/kg enhanced immune surveillance by increasing circulating IgY levels, maintaining a normal oxidative state, and increasing gut Bifidobacteria, thereby improving chick growth performance. [ABSTRACT FROM AUTHOR]