The presence of fluoroquinolone (FQ) residues in food-producing animals has raised concerns regarding antimicrobial resistance. This study evaluated the occurrence of FQ residues in the liver and kidneys of piglets and their association with resistance patterns in and species from piglets' intestinal microbiota. FQ residues were found in 44% of livers and 23% of kidneys. Among 340 isolates from feces, resistance to ciprofloxacin (CIP) (43.2%) and multidrug resistance (MDR) (82.7%) were prominent. The presence of FQ in kidneys significantly increased the odds of CIP-resistant (OR = 2.94, = 0.0013) and MDR (OR = 2.70, = 0.0047). Enterococci ( = 130) were evenly distributed among the species , , and spp. and presented resistance to CIP (34.6%). FQ in kidneys were associated with higher odds of CIP-resistant enterococci (OR = 3.78, = 0.015). Interaction models revealed species-dependent responses, with spp. showing high resistance in the presence of FQ in kidneys (OR = 18, = 0.006), while exhibited lower resistance compared to . These findings emphasize the role of FQ residues in promoting bacterial resistance and underscore the need for the stricter regulation and routine surveillance of antimicrobial use in livestock to curb the spread of bacterial resistance to clinical drugs, and mitigate public health risks-One Health.