Heterogeneous catalysis performs on specific sites of a catalyst surface even if specific sites of many catalysts during catalysis could not be identified readily. Design of a catalyst by managing catalytic sites on an atomic scale is significant for tuning catalytic performance and offering high activity and selectivity at a relatively low temperature. Here, we report a synergy effect of two sets of single-atom sites (Ni-1 and Ru-1) anchored on the surface of a CeO2 nanorod, Ce0.95Ni0.025Ru0.025O2. The surface of this catalyst, Ce0.95Ni0.025Ru0.025O2, consists of two sets of single-atom sites which are highly active for reforming CH4 using CO2 with a turnover rate of producing 73.6 H-2 molecules on each site per second at 560 degrees C. Selectivity for producing H-2 at this temperature is 98.5%. The single-atom sites Ni-1 and Ru-1 anchored on the CeO2 surface of Ce0.95Ni0.025Ru0.025O2 remain singly dispersed and in a cationic state during catalysis up to 600 degrees C. The two sets of single-atom sites play a synergistic role, evidenced by lower apparent activation barrier and higher turnover rate for production of H-2 and CO on Ce0.95Ni0.025Ru0.025O2 in contrast to Ce0.95Ni0.05O2 with only Ni-1 single-atom sites and Ce0.95Ru0.05O2 with only Ru-1 single-atom sites. Computational studies suggest a molecular mechanism for the observed synergy effects, which originate at (1) the different roles of Ni-1 and Ru-1 sites in terms of activations of CH4 to form CO on a Ni-1 site and dissociation of CO2 to CO on a Ru-1 site, respectively and (2) the sequential role in terms of first forming H atoms through activation of CH4 on a Ni-1 site and then coupling of H atoms to form H-2 on a Ru-1 site. These synergistic effects of the two sets of single-atom sites on the same surface demonstrated a new method for designing a catalyst with high activity and selectivity at a relatively low temperature.