Salmonella enterica subsp. enterica (Salmonella), one of the most common causes of bacterial foodborne infections, causes salmonellosis, which is usually self-limiting. However, immunocompromised individuals and children often require antimicrobial therapy. The first line of treatment includes fluoroquinolones, to which Salmonella has emerging resistance worldwide. In fact, the WHO classified fluoroquinolone-resistant Salmonella as a high-priority pathogen. Salmonella carrying genes such as blaCTX and blaCMY can show resistance to cephalosporins which are also regularly used for treatment. This study focused on determining the antimicrobial resistance of 373 Salmonella isolates, collected from various foods, humans, and animals, as well as the environmental sludge between 2005 and 2020 in Türkiye. Phenotypic analysis of the resistance was determined by disk diffusion method. Isolates resistant to any of the following: ciprofloxacin, pefloxacin, azithromycin, and ceftriaxone were tested for the presence of quinolone, beta-lactamase, and/or macrolide resistance genes by PCR and gel electrophoresis. Five multi-drug-resistant isolates were then further whole genome sequenced and analyzed. More than 32% (n = 120) of the isolates showed resistance to fluoroquinolones by disc diffusion. A significant number of quinolone-resistant isolates are presented with mutated parC and gyrA. Furthermore, 42% (n = 106) of the isolates were resistant to azithromycin and 10% of them harbored mphA gene. On the bright side, only eight isolates showed resistance to ceftriaxone. Overall, we observed an increase in the number of isolates showing resistance to fluoroquinolones and azithromycin over the years and low resistance to ceftriaxone.