Streptococcus suis an opportunistic porcine pathogen that can cause severe disease in humans, most commonly meningitis and sepsis. S. suis is classified into 29 distinct serotypes based on the structure of its capsular polysaccharide, however, ~95% of the reported infections in humans have been caused by serotype 2 (st2) isolates. The mechanism behind the overrepresentation of st2 in zoonotic infections remains unclear. We combined Bayesian evolutionary models and multivariate analysis to statistically demonstrate the contribution of the st2 capsule in enabling zoonotic infections and the emergence of novel zoonotic lineages. We used isogenic serotype switched mutants for the main pathogenic serotypes in several in vitro models of human infection to unveil the precise mechanism by which the st2 capsule facilitates zoonosis. Carrying a st2 capsule was statistically associated with zoonotic potential, and acquisition of the st2 capsule through capsular switching led to the emergence of three novel zoonotic lineages. The st2 isogenic mutant was the most resistant to killing in a human whole-blood killing assay and survived opsonophagocytosis by human neutrophils. These phenotypes were not caused by evading the complement system as the st2 strain was completely opsonized in a complement deposition assay. Instead, the st2 capsule interacted through its terminal sialic acids with the inhibitory human receptors Siglec-2 and Siglec-10. Since Sigcles are expressed on a wide range of immune cells, this interaction may enable st2 S. suis to broadly downregulate human immune responses thus explaining its predominance in zoonotic infections.