Fruit yield and quality improvement are challenges for researchers and farmers. This study reveals that the main fruit traits of blueberry (Vaccinium ashei ‘Bluegem’) were significantly improved after hydrogen (H₂)-based irrigation, assessed by the increased single fruit weight (14.59 ± 6.66%) and fruit equatorial diameter (4.19 ± 2.39%), decreased titratable acidity, increased solid–acid and sugar–acid ratios. The enhancement of fruit quality was confirmed by the increased total volatiles, vitamin C contents, and antioxidant capacity. Using weighted protein co-expression network analysis (WPCNA), proteomic interrogation revealed that serine carboxypeptidase-like proteins I/II (SCPLI/II), ADP ribosylation factor 1/2 (ARF1/2), and UDP-glucosyltransferase 85A (UGT85A) might be functionally associated with the increased fruit weight and size driven by H₂. Reduced organic acid accumulation was caused by the regulation of the specific enzymes involved in sucrose metabolism (e.g., α-amylase, endoglucanase, β-glucosidase, etc.). H₂ regulation of fatty acid degradation (e.g., acyl CoA oxidase 1 (ACX1), acetyl CoA acyltransferase 1 (ACAA1), etc.) and phenylpropanoid metabolism were used to explain the improved fruit aroma and anthocyanin accumulation. Meanwhile, the upregulated heat shock protein 20/70 matched with the enhanced antioxidant activity. Together, this study provides a novel approach for yield and quality improvement in horticultural crops.