Oxygen mass transfer in non-Newtonian fluids represents a key rate-limiting step in aerobic biopolymer fermentations. To enhance mass-transfer performance, a novel chaotic reactor (CHR) featuring tri-axial impellers was proposed and optimized using validated computational fluid dynamics (CFD) modeling. The impacts of pumping mode, impeller rotational speeds, and chaotic flow characteristics on the volumetric mass-transfer coefficient (kLa) and power consumption (P) were systematically investigated. The CFD model demonstrates average relative deviations of 5.7% and 12.6% in predicting bubble coalescence/breakup behavior and kLa-P relationships. The optimized CHR, configured with down-pumping operation for both bottom and top pitched-blade impellers, achieved 131% higher process efficiency than that of the conventional coaxial reactor when processing 1.0% carboxymethyl cellulose solution. The mechanism is attributed to the formation of a large-scale horizontal vortex and effective chaotic flow at Reynolds numbers (Re) exceeding 17.5. These findings provide new insights for rational optimization in aerobic bioprocess fermentations.