A comparative experimental and numerical study has been conducted on the flow and heat transfer characteristics in a latticework cooling channel with U-shaped subchannels combined with dimple vortex generators over the Reynolds number range of 7700–36,985. The average Nusselt number and friction factor of the latticework channel have been obtained. The comparisons between the experimental and numerical data have shown that the numerical computation model can reasonably well predict the heat transfer and pressure loss in the latticework cooling channels. Additional numerical computations were further performed to investigate the effects of subchannel configurations on the flow and heat transfer in the latticework channel, and three different subchannel configurations were studied, which are the dimpled U subchannel, U subchannel, and rectangular subchannel. The experimental data of the heat transfer and pressure loss of the latticework channel with dimpled U subchannels have also been compared with those of the ribbed channels and pin fin channel from the literature. The present study indicated that the superior heat transfer enhancement capability of the latticework cooling is mainly due to the remarkably increased heat transfer area, turning effects producing strong vortical flow in the subchannels, and the interactions between the flow in the crossing subchannels, as well as the interactions between the flow and the crossing ribs on the opposite side.