Sweet cherry (Prunus avium L.) is a valuable fruit crop worldwide. Farmers’ incomes are closely related to fruit quantity and quality, yet these can be highly variable across years. As part of a broader project for optimizing fruit set and fruit quality in sweet cherries, this study was conducted to evaluate the potential of various plant growth regulators (PGRs) for improving fruit set and fruit quality. Cytokinins, gibberellins, auxin, and polyamines were used as treatments. Treatments were applied as foliar sprays at full bloom to ‘Bing’ and three low-productivity genotypes, ‘Regina’, ‘Tieton’, and ‘PC8011-3’. We assessed the fruit set, fruit quality, and return bloom from each treatment. 4-chlorophenoxyacetic acid (4-CPA) increased fruit set by 53% and 36% in ‘Bing’ and ‘Tieton’, respectively. The combination of gibberellin (GA)3 + GA4/7 was more effective for improving fruit set than other isomers of gibberellin alone. Cytokinin treatments had slight adverse effects or no effect on fruit set except for CPPU. In ‘PC8011-3’, both N-(2-chloro-4-pyridyl)-N'-phenylurea (CPPU) and 4-CPA enhanced fruit set by ≈81% and 100% compared with untreated control. The response of cherry trees to polyamine sprays depended on the properties of the cultivars and the treatment concentration. Foliar application of GA3, GA4/7, or N-phenyl-N'-(1, 2, 3-thiadiazol-5-yl) urea (TDZ) in ‘Bing’ trees has negative effects on return bloom, whereas GA1 can increase the yield and flower buds. These results suggest that PGRs may have varied effects on sweet cherry fruit set and that more work is needed to develop practical programs for improving yield security.