Understanding the facet-dependent adsorption behavior and mechanism of heavy metal ions (HMs) on two-dimensional (2D) Janus nanoclays has important implications for the environment and ecosystem but still remains elusive. Herein, ultrathin Janus serpentene (2D serpentine) nanosheets were fabricated via a facile, nontoxic, and residue-free exfoliation strategy. Fabricated serpentene nanosheets exhibited promising Cd(II) and Pb(II) adsorption capacities due to their high surface areas and abundant active sites, approximately four times higher than those of bulk serpentine powders. Interestingly, Cd(II) and Pb(II) adsorption on serpentene nanosheets exhibited a facet-dependent feature, with the adsorption amount on the Mg–OH plane considerably higher than that on the Si–O plane. This facet-dependent adsorption behavior was mainly attributed to the difference in the interaction mechanisms of HMs with the Mg–OH (monodentate inner-sphere complexation) and Si–O (outer-sphere complexation) planes, which was further confirmed via density functional theory calculations. The Cd(II) adsorption on serpentene nanosheets was limited by strong kinetic restrictions (e.g., stronger electrostatic repulsion and higher dehydration energy barrier than that for Pb(II) adsorption). This study provides insights into the facet-dependent adsorption mechanisms of HMs on Janus serpentene nanosheets, which can be extended to other nanoclays used in wastewater treatment and many environmental processes.