This study aimed to investigate the eco-toxicological responses of earthworm ( Eisenia fetida ) exposed to combined siduron (herbicide) and cadmium (Cd). Eisenia fetida gene expressions including metallothionein (MT) and heat shock protein70 (Hsp70) were analyzed using real-time Polymerase Chain Reaction after individual and combined siduron (0.90, 1.80, 3.60 and 7.20 μg cm − 2 ) and Cd (0.225, 0.45, 0.90 and 1.80 μg cm − 2 ) sublethal exposures. Where, the nature of the toxicological interactions between siduron and Cd in inducing or suppressing MT and Hsp70 expression was determined by applying the Combination index (CI)-isobologram model. The results revealed significant variations in MT and weak changes in Hsp70 expression when the earthworms were exposed to individual Cd. The individual siduron exposure exhibited a significant down-regulation ( p < 0.01) in MT during all treatments and in Hsp70 expression only at 7.20 μg cm − 2 concentration; while the mixtures of siduron and Cd exposures resulted a significant down regulation ( p < 0.05) in both MT and Hsp70 expressions. Moreover, the combined siduron and Cd exposure revealed nearly additive effect (CI = 1) at the lower effect levels and significant synergistic effect (CI < 1) at the higher effect levels for both MT and Hsp70 expression. The synergistic effects of combined siduron and Cd suggest that there might be a potential risk connected to the co-occurrence of these chemicals in the environment. [ABSTRACT FROM AUTHOR]