Salmonella enterica is a major food-borne pathogen that affects cattle-rearing systems worldwide. Little information is available on the epidemiology and pathology of salmonellosis and the virulence genes (VGs) carried by Salmonella in spontaneous outbreaks in cattle. We describe epidemiological findings in 15 fatal outbreaks of salmonellosis in Uruguayan dairy farms and the age, clinical signs, and pathology in 20 affected calves. We also describe the serotypes and frequencies of 17 VGs in the causative Salmonella strains and explore their associations with epidemiological, clinical, and pathological findings. Salmonella Typhimurium and Dublin were identified in 11/15 and 4/15 outbreaks, respectively. The most frequent reason for consultation was digestive disease (8 outbreaks caused by S. Typhimurium), followed by sudden death (4 outbreaks, 3 caused by S. Dublin). Morbidity, mortality, and lethality ranged 4.8-100%, 3.8-78.9%, and 10-100%, without significant differences between serotypes. Diarrhea, the most common clinical sign (14 cases), was associated with the Typhimurium serotype (OR = 26.95), especially in ≤ 30-day-old calves with fibrinous enteritis as the main autopsy finding. The Dublin serotype affected ≥ 50-day-old calves and was associated with fibrinosuppurative splenitis (p = 0.01) and tubulointerstitial nephritis (OR = 48.95). The chances of the Dublin serotype increased significantly with age. There was low variability of VG across serotypes. The pefA gene was associated with the Typhimurium serotype (OR = 21.95), macroscopic enteritis (p = 0.03), and microscopic fibrinosuppurative splenitis (p = 0.04). Understanding the epidemiology, pathology, and virulence of S. enterica at the farm level is key to delineating prevention and control strategies to mitigate its impact on animal and human health.