The ‘Feizixiao’ litchi cultivar, predominantly grown in Hainan Province, faces the issue of “sugar receding” during fruit ripening. The application of mixed foliar nutrients containing calcium and magnesium (Ca+Mg) during the fruit pericarp’s full coloring stage was investigated to overcome this issue. Experimental trials unveiled significant alterations in litchi pulp physiochemical properties, including the main nutrient and flavor quality, the total respiration rates of the main respiratory pathways, and the activities of some important enzymes associated with Embden–Meyerhof–Parnas (EMP), the tricarboxylic acid cycle (TCA) and the pentose phosphate pathway (PPP). The Ca+Mg treatment showed higher sugar levels than the control (CK) during ripening. Notably, the application of Ca+Mg in litchi pulp inhibited respiration rates through the EMP, TCA, and PPP pathways, resulting in a strong effect. RNA sequencing analysis revealed the impact of Ca+Mg treatment on respiratory pathways, revealing differentially expressed genes (DEGs) such as pyruvate PK1, PK2 (pyruvate kinase), and PDC (pyruvate dehydrogenase complex), validated through qRT-PCR with a significant correlation to RNA-seq results. In general, Ca+Mg treatment during litchi fruit ripening overcame “sugar receding” by inhibiting the expression of respiration key metabolic pathway genes. These findings provide insights for enhancing cultivation management strategies.