Salmonella enterica relies on translocation of effector proteins through the SPI-2 type III secretion system (T3SS) for pathogenesis. More than 30 effectors contribute to manipulation of host cells through diverse mechanisms, but interdependency or redundancy between effectors complicates the discovery of effector phenotypes using single mutant strains. Here, we engineered six mutant strains to be deficient in groups of SPI-2 effectors, as defined by their reported function. We deployed these strains in various animal models of infection and discovered three main effector groups define the functional contribution of the SPI-2 T3SS to infection. Multimutant strains deficient for intracellular replication, for manipulation of host cell defences, or for expression of virulence plasmid effectors all show strong attenuation in vivo, while mutants representing approximately half of the known effector complement show phenotypes similar to the wild-type parent strain. By additionally removing the SPI-1 T3SS, we find groups of effectors that contribute to SPI-2 T3SS-driven enhancement of gut inflammation. During antibiotic treatment, we found SPI-2 to be unexpectedly dispensable for antibiotic survival, but effectors contributing to intracellular replication were essential for bacterial recovery after withdrawal of antibiotic therapy. Surviving bacteria were able to exploit antibiotic-mediated disruption of the gut microbiota, facilitating robust and clonal gut colonisation and transmission to susceptible new hosts. Co-housing infected mice with naïve cagemates prevented transmission of recovering persisters, and 16S analysis confirmed the transfer of microbiota between cagemates as the protective mechanism, highlighting how bacterial transmission is shaped by the pathogen-host-microbiota axis. Ultimately, we provide new insights into how Salmonella virulence factors support within-host colonisation and between-host transmission, with consequences for how antibiotics are used to control infection.