Background: Antibacterial agents play important roles in the treatment of bacterial infections. However, the development of antimicrobial resistance (AMR) and carry-over of substances into the environment are several problems arising during oral treatment of bacterial infections. We assessed AMR development in commensal Escherichia coli (E. coli) in enrofloxacin treated and untreated animals. In addition, we examined fluoroquinolone in the plasma and urine of treated and untreated animals, and in sedimentation dust and aerosol. Methods: In each trial, six pigs were treated with enrofloxacin via powder, granulate or pellet forms in two time periods (days 1–5 and 22–26). Four pigs served as untreated controls. The minimum inhibitory concentration (MIC) was determined to evaluate AMR development. Analysis of enro- and ciprofloxacin was performed with high performance liquid chromatography. Results: Non-wildtype E. coli (MIC > 0.125 µg/mL) was detected in the pellet treated group after the first treatment period, whereas in the other groups, non-wildtype isolates were found after the second treatment period. E. coli with MIC > 4 µg/mL was found in only the pellet trial. Untreated animals showed similar susceptibility shifts several days later. Bioavailability differed among the treatment forms (granulate > pellet > powder). Enro- and ciprofloxacin were detected in aerosols and sedimentation dust (granulate, powder > pellet). Conclusions This study indicates that the kind of the oral dosage form of antibiotics affects environmental contamination and AMR development in commensal E. coli in treated and untreated pigs.