In viticulture, the main target is to achieve high yield and good fruit quality without compromising vine growth. Methods to achieve this balance will vary with regard to climate and cultivar. A two-year study was conducted on five-year-old ‘Prime Seedless’ grapevines to evaluate the effect of leaf defoliation and the foliar application of low-biuret urea (LBU) and cyanocobalamin (CCA) on berry set percentage, the compactness coefficient of the clusters and the overall quality of clusters and berries. The removal of the first four basal leaves was conducted at the full-bloom (FB) stage, while LBU (5 g·L−1) and CCA (40 mg·L−1) were sprayed at three phenological stages: (1) when the cluster length reached ~10 cm long, (2) at FB and (3) one week after the fruit set. The results demonstrated that the sole application of basal leaf removal (BLR) or in combination with LBU and/or CCA improved the vegetative growth, total yield and physiochemical characteristics of clusters and berries, whereas the same treatments decreased berry set and shot berry percentages and the compactness coefficient of the clusters, which in turn led to looser clusters compared to the control. The most pronounced effect was recorded for the combined application of BLR, LBU and CCA, which revealed the highest values of shoot length, leaf area and the contents of chlorophyll, proline, N, P, K, Ca, Mg, Fe and Zn. The same treatment recorded the lowest berry set and shot berry percentages, compactness coefficient of clusters and decay percentage. Overall, this treatment was the best in terms of total yield, cluster weight, berry firmness, soluble solid content (SSC), the SSC/acid ratio, total sugars, total carotenoids, total phenols, phenylalanine ammonialyase and polyphenol oxidase.