Non-typhoidal Salmonella (NTS) represents a growing public health concern worldwide due to its increasing antimicrobial resistance and substantial disease burden, yet data from Romania remain limited. We conducted the first regional 7-year retrospective study of NTS-associated diarrhea among hospitalized patients, focusing on resistance trends and clinical factors associated with disease severity. This study included all laboratory-confirmed Salmonella infections admitted for acute diarrheal disease to the “Sfânta Parascheva” Clinical Hospital of Infectious Diseases, Iași (January 2018–December 2024). Patient data were extracted from electronic medical records and analyzed using SPSS (v31.0), with statistical significance set at p < 0.05. Among the isolates obtained from the 698 included patients, most belonged to serogroup D (63.6%), followed by B (21.8%) and C (14.0%). Overall resistance rates were 12.3% for ampicillin, 3.6% for trimethoprim–sulfamethoxazole and 29.9% for ciprofloxacin, with a significant yearly increase observed only for ciprofloxacin (OR = 1.21, p < 0.001). Cardiovascular comorbidities were independently associated with prolonged hospitalization (>5 days) (OR = 2.25, p = 0.007). Invasive infections occurred in 14 patients (2%). Given the high ciprofloxacin resistance and the additional impact of comorbidities on disease severity, there is a need for ongoing surveillance and targeted management strategies.