Background/Objectives: This study aimed to understand the extent of transmission of antibiotic residues from treated to untreated pigs and the barn environment using different pen set-ups. This is in order to create awareness and to stimulate prudent use of antibiotics in livestock farming. Methods: Transmission, expressed as the (relative) residue level, of sulfadimidine, enrofloxacin and its metabolite ciprofloxacin was determined using animal wipes, surface wipes and manure samples of pigs in four different compartments with variations in interconnected or distanced pens and type of pen partitions (open or closed). Results: Most antibiotic residues in untreated pigs were detected with a combination of open partitions and interconnected pens. Separating the pens with space in between minimized detectable antibiotic residues in the manure of untreated pigs, whereas interconnected pens did show antibiotic residues in internal matrices. Antibiotic residues were detected in the barn environment after treatment in all different pen set-ups. Conclusions: After treatment, transmission of antibiotic residues occurred in the barn environment and in the untreated pigs housed in the same barn. The spatial distribution of residues suggests that airborne dust and/or aerosols may be important routes of external transmission. Results under these experimental conditions indicate that restricting physical contact between treated and untreated pigs may be an important strategy for reducing antibiotic residues in internal matrices. This set-up also showed lower external residue levels, especially when closed partitions are used.