We report the significant enhancement of the power factor of Ca3Co4O9+δ through Yb doping. The pellets were prepared by pressing under 0.5 GPa and 2 GPa. The highest power factor of 553 μW m−1 K−2 due to the significant increase of electrical conductivity was obtained for Ca2.9Yb0.1Co4O9+δ pressed at 0.5 GPa. This is 2.3 times higher than that of Ca3Co4O9+δ (246 μW m−1 K−2). Nanostructure examinations show that the pellets pressed at 0.5 and 2 GPa have different nano-lamella structures. This work suggests that Yb is an effective doping element for enhancing the electrical transport properties of Ca3Co4O9+δ, and the optimum doping level is related to the nanostructure of the bulk pellets.