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Spray-drying production of litchi powder is frequently constrained by low yield and unstable quality, largely attributable to variations in fruit sugar–acid profiles. To elucidate the compositional factors affecting powder performance, ten litchi cultivars with distinct sugar–acid ratios were processed under identical conditions. Baitangying produced superior powder with the highest yield (89.23±1.25%), solubility (98.17±0.49%), and glass transition temperature (52.17±2.00 ℃). Jizuili also performed well. Both high-sucrose, low-acidity cultivars demonstrated excellent drying efficiency and storage stability. Conversely, high-acid and reducing-sugar cultivars (Feizixiao, Guanxiangli) retained more moisture (> 7%) and showed lower glass transition temperature, suggesting inferior stability. Correlation analysis revealed that fructose (ρ = −0.794, p < 0.001) and titratable acidity (ρ = −0.770, p < 0.001) were negatively correlated with yield, while sucrose was positively associated with yield and color lightness (ρ = 0.630, p < 0.05). Antioxidant capacity varied among cultivars and was mainly governed by total phenolics and litchi thaumatin-like protein, with Feizixiao and Jingganghongnuo showing the highest FRAP values (19.36 ± 0.12 and 17.38 ± 0.33 μg TE/mg DW). Overall, intrinsic sugar–acid profiles fundamentally determine the drying efficiency, powder stability, and bioactive retention of litchi powder.