<p>Cadmium (Cd) stress considerably reduces crop yield. The use of biostimulants, like humic substances (HS), is a research strategy for increasing Cd tolerance. The present study evaluated the effectiveness of a HS-based product in improving Cd tolerance in lettuce. It was selected for its ability to enhance growth through improved photosynthesis and antioxidant capacity although its effectiveness under Cd stress is unclear. The study also investigated which mode of HS application (to roots or leaves) is more effective in enhancing Cd tolerance and reducing Cd accumulation. Plants were grown under Cd stress (100 µM CdCl₂), Cd stress + HS applied to the roots (R-HS) at 0.40 and 0.60 mL/L, and HS applied to the leaves (F-HS) at 7.50 and 10.00 mL/L, alongside a control (no CdCl₂). R-HS involved irrigating pots with HS diluted in a nutrient solution, whereas F-HS consisted of spraying leaves with HS diluted in distilled water. Cd reduced shoot and root dry weight (DW) by 35%. However, a lower reduction was observed under HS applications (16%, 22%, 19%, and 18% at R-HS 0.40 and 0.60 mL/L, and F-HS 7.50 and 10.00 mL/L, respectively). These results were attributed to increased antioxidant capacity, thiol biosynthesis, and photosynthesis activity. While the application mode did not affect the Cd tolerance, R-HS 0.60 mL/L increased shoot Cd (21%), whereas F-HS 10.00 mL/L reduced it (14%). Our study indicates that the HS-based product could enhance Cd tolerance in lettuce at the tested doses. In addition, R-HS 0.60 mL/L may be effective for Cd phytoextraction, whereas F-HS can help reduce Cd accumulation in leaves.</p>