Irrational prescribing can compromise patient safety, medicine availability, and antimicrobial stewardship. At a public district hospital in southwestern Uganda, a 2019 internal audit prompted by recurrent stock-outs found approximately three medicines per outpatient prescription, four per inpatient prescription, and antibiotics in about 60% of outpatient prescriptions. We implemented a six-month quality improvement initiative to increase prescribing concordant with the Uganda Clinical Guidelines (UCG) and improve key indicators of rational medicine use among outpatients. From January to November 2021, we conducted an uncontrolled before-and-after quality improvement evaluation. Prescription records were selected by systematic random sampling at baseline and six-month endline. We reviewed 350 baseline and 101 endline outpatient prescriptions. The primary outcome was prescription concordance with UCG. Secondary outcomes included antibiotic prescribing, number of medicines per encounter, generic prescribing, and injection use. Adjusted analyses accounted for age, sex, and diagnostic group. Following root-cause analysis, the hospital quality improvement (QI) team implemented prescriber education, provided clinicians with soft-copy PDF versions of the UCG and essential medicines lists, restricted prescribing to recognized clinicians with signature verification, and instituted periodic prescription audit and feedback. Guideline-concordant prescribing increased from 43.7% to 76.2% (adjusted change, +32.8 percentage points; 95% CI, 21.9–43.8; aPR=1.82; 95% CI, 1.51–2.20). Antibiotic prescribing decreased from 83.4% to 65.3% (adjusted change, −17.9 points; 95% CI, −27.8 to −8.0; aPR=0.80; 95% CI, 0.70–0.91). Mean medicines per encounter decreased from 3.35 to 2.66 (adjusted mean difference, −0.61; 95% CI, −0.79 to −0.43), while prescriptions containing only generic medicines increased from 78.6% to 94.1% (adjusted change, +13.6 points; 95% CI, 5.8–21.4). Guideline-concordant prescribing increased, while antibiotic use and medicine burden declined and generic prescribing improved. Antibiotic use nevertheless remained high, underscoring the need for continued stewardship, audit, and iterative QI.