The causal relationship between mitochondrial DNA copy number (mtDNA-CN) and intervertebral disc degeneration (IVDD) remains unclear. The study aimed to investigate the causal relationship between mtDNA-CN and IVDD using Mendelian randomization analyses.The causal relationship between mtDNA-CN and IVDD was estimated using a bidirectional two-sample Mendelian randomization (MR) method. The inverse-variance weighted (IVW) method was employed as the main MR method. Sensitivity analyses were conducted to validate the robustness and reliability of the MR results.The MR results by IVW revealed that genetically predicted mtDNA-CN was not associated with IVDD (OR = 0.91, 95% CI = 0.79-1.04, P = 0.1731). Similar results were observed in other four MR methods (P > 0.05). Heterogeneity was found in the analysis of IVDD on mtDNA-CN (P < 0.05), while no horizontal pleiotropy was observed (P > 0.05). Furthermore, the leave-one-out analysis indicated the robustness of MR results not biased by a single SNP. Moreover, the reverse MR analysis did not reveal any significant causal association of IVDD on mtDNA-CN.The study revealed that there is no causal relationship of mtDNA-CN on the risk of IVDD, nor does IVDD have a significant causal effect on mtDNA-CN. Although the study did not find a significant causal relationship, it provides valuable insights into the complex interplay between genetic factors and IVDD. Further research is needed to explore to better understand the underlying mechanisms of this condition.Copyright © 2025. Published by Elsevier Inc.