A two-dimensional (2D) Sb-modified screen-printed carbon nanofibers electrode (2D Sbexf-SPCNFE) was developed to improve the stripping voltammetric determination of Cd(II) and Pb(II), taking advantage of the synergistic effect between the two nanomaterials. The surface morphology of the 2D Sbexf-SPCNFE was investigated by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and Raman spectroscopy. The analytical performance of 2D Sbexf-SPCNFE was compared to those presented by screen-printed carbon electrodes modified with 2D Sbexf (2D Sbexf-SPCE) and the corresponding bare electrodes: screen-printed carbon nanofibers electrode (SPCNFEbare) and screen-printed carbon electrode (SPCEbare). After optimizing the experimental conditions, the 2D Sbexf-SPCNFE exhibited much better analytical parameters compared to the other assessed sensors. Analysis in 0.01 mol L−1 HCl (pH = 2) using 2D Sbexf-SPCNFE showed excellent linear behavior in the concentration range of 2.9 to 85.0 µg L−1 and 0.3 to 82.0 µg L−1 for Cd(II) and Pb(II), respectively. The limits of detection after 240 s deposition time for Cd(II) and Pb(II) were 0.9 and 0.1 µg L−1, and sensitivities between 1.5 and 3 times higher than those displayed by SPCEbare, SPCNFEbare, and 2D Sbexf-SPCE were obtained. Finally, the 2D Sbexf-SPCNFE was successfully applied to the determination of Cd(II) and Pb(II) traces in a certified estuarine water sample.