Extracellular ATP (eATP) has recently been considered important in signaling against abiotic stress in plants. However, the potential advantageous mechanisms of eATP in a plant's adaptation to cadmium (Cd) stress are largely unknown. In the present study, using eATP-insensitive mutants, does not respond to nucleotides 1–3/4, we investigated the possible roles and regulatory effects of eATP in mitigating Cd2+ toxicity in Arabidopsis thaliana. The results show that dorn1–3 and dorn1–4 possessed lower germination and root length, but exhibited higher relative electrolyte leakage than those in wildtype (WT) under Cd stress. In addition, CdCl2 caused a marked trend of first increase and then decrease in eATP within the three strains during 24 h of treatment. The Cd2+-induced Cd2+ influx in the roots of dorn1–3 and dorn1–4 was notably higher than that in WT, whether in steady or in transient states. Additionally, the application of exogenous ATP-Na2 (an eATP donor) reduced but exogenous PPADS (a specific inhibitor of P2K1) increased the Cd2+-elicited Cd2+ influx. The fluorescence intensities of Cd2+ and H2O2 in the mutants were also notably higher than those in WT. Furthermore, H2O2 signaling could be activated via eATP signaling and inhibit Cd2+ intry under Cd conditions. Under Cd stress, eATP-triggered H2O2 signaling seemed to activate the downstream transcription of genes involved in the antioxidant system, such as AtGR1, AtCAT1, AtGPX8, and AtSOD1/2, and downregulate the relative levels of AtIRT1 and AtIRT2 transcripts. To sum up, through binding to its receptor, P2K1, the Cd-elicited eATP potentially activated the downstream signal H2O2, which could further inhibit Cd entry by downregulating the expression of AtIRTs and remove excess ROS via upregulating genes involved in the antioxidant system, eventually leading to the mitigation of Cd toxicity.