Background Although Beef Quality Assurance guidelines do not recommend use of darting methods to deliver drugs, cattle in the US may be raised on farms and ranches without restraint facilities, and reports from the field suggest that dart guns are being used to deliver antimicrobial drugs. Few studies report whether this route of administration results in altered drug disposition or carcass quality. Methods Forty steers were blocked by sire and then randomly assigned to treatment with saline, ceftiofur crystalline free acid, tildipirosin, or tulathromycin delivered via dart gun. To assess drug disposition, eight ceftiofur, six tulathromycin, and six tildipirosin-treated calves were selected to measure plasma concentrations of drugs up to 10 days after drug administration. Steers were then fed a balanced ration for approximately 6.5 months and slaughtered. To evaluate carcass quality, tenderness of steaks from darted-side and non-darted sides was evaluated via Warner-Bratzler shear force testing. Due to the prohibition of extralabel routes of administration for ceftiofur in the U.S., animals treated with this drug did not enter the food supply. Results Ceftiofur disposition differed from published reports with lower mean C.sub.max but similar mean apparent elimination half-life. Tildipirosin disposition differed from published reports with lower C.sub.max and shorter apparent elimination half-life. Tulathromycin was similar to previous published reports but C.sub.max and apparent elimination half-life was highly variable. All steaks (from darted and non-darted sides) from cattle treated with ceftiofur and saline were more tender than from cattle treated with tulathromycin or tildipirosin (P = 0.003). There was a trend toward more tenderness in steaks from the non-darted compared to the darted side. Steaks from the darted side for one treatment, tildipirosin, were less tender than the non-darted side. Conclusions Pharmacokinetic parameters of ceftiofur crystalline free acid, tildipirosin, and tulathromycin to cattle using pressure-adjustable pneumatic gas-powered dart gun were estimated in this study. Delivery of tildipirosin and tulathromycin to cattle with dart gun may also result in detectable decreases in tenderness of harvested steaks.