Heavy metals are considered as hazardous substances to human because of their toxicity, persistence and bioaccumulation, and the level in serum is an important factor to evaluate the caused health risk, which depends on efficient and sensitive analytical methods. Here, a triple signal-amplified electrochemical sensing platform based on metal-dependent DNAzymes was fabricated for sensitive determination of heavy metals in serum (copper as a model target). Under the optimized conditions, the proposed method showed good sensitivity (limit of detection, 0.33 fM for Cu2+) with excellent selectivity and stability, which is ascribed to: (i) tetrahedral DNA nanostructures (TDNs) that was used as a promising scaffold to adjust the selective transformation between heterogeneous and homogeneous reactions, preventing the nonspecific binding of electrodes surface and DNA probes; (ii) the magnetic beads (MBs) used which led to signal amplification and decreased background owing to its excellent properties of extracting equivalent targets from the complex samples; (iii) two signal amplification strategy of catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR). In addition, the proposed sensing platform displayed satisfactory accuracy through the validation with inductively coupled plasma-mass spectrometry (ICP-MS) and a spike-recovery analysis (recoveries, 87.92-111.61%; RSD, 4.89-8.85%), indicating the great potential for rapid and sensitive detection of Cu2+ or other metal ions.