Diarrhea is the fourth leading cause of child mortality in Ghana. In 2010, Ghana endorsed guidelines from the World Health Organization and the United Nations Children’s Fund for use of zinc with low-osmolarity oral rehydration salts (ORS) for the treatment of acute childhood diarrhea. From late 2011 through 2014, the Strengthening Health Outcomes through the Private Sector (SHOPS) project implemented a comprehensive program in 3 regions of Ghana to increase the availability and use of ORS and zinc and to decrease incorrect use of antibiotics and antidiarrheals. The program included (1) partnering with local pharmaceutical firms to introduce and market locally produced zinc products, (2) collaborating with the Ghanaian Pharmacy Council to provide training and supportive supervision of private-sector providers on diarrhea management, and (3) conducting mass media campaigns to raise caregiver awareness. We evaluated the effect of this program using a baseline survey of 754 caregivers of children under 5 with diarrhea at the start of the intervention in 2012 and a follow-up survey of 751 caregivers in 2014. Regression analysis showed that use of ORS with zinc increased from 0.8% in 2012 to 29.2% in 2014 (P<.001), and antibiotic use declined from 66.2% to 38.2% (P<.001) during the same period. The magnitude and statistical significance of these results remained the same after including potential confounding factors as covariates. Inappropriate antibiotic use, however, remained high at follow-up. We conclude that similar programs applied in other settings have the potential to rapidly scale up use of ORS and zinc. Additional efforts are required to reduce persistent incorrect antibiotic use.