An assay for measuring Serpin B12 in porcine saliva was developed and validated, showing adequate precision, accuracy, and sensitivity. Changes in salivary Serpin B12 concentrations were evaluated under different conditions, including the time of the day, the productive cycle, experimental sepsis and non-septic inflammation, S. suis infection and stress. Serpin B12 were significantly higher at 4 p.m. compared to other times of the day and were higher in piglets before the end of the nursery phase. Significant increases were detected at 6 h and 24 h after the intramuscular administration of Escherichia coli lipopolysaccharide in pigs and in pigs naturally infected with Streptococcus suis. Non-septic inflammation, induced by subcutaneous administration of turpentine oil and stress caused by transport and a 4 h lairage at the slaughterhouse, also resulted in increased Serpin B12 levels, although these increases were less pronounced than those observed in sepsis. In conclusion, the developed assay effectively measures Serpin B12 in saliva, and its concentrations vary depending on sampling time and animal age. In addition, salivary Serpin B12 increases in situations of sepsis, non-septic inflammation, and stress, with the most substantial changes associated with septic conditions.