Objective To explore the association between plasma proteins and the risk of Addison’s disease using the Mendelian randomization (MR) method. Methods Plasma protein quantitative trait loci data from the deCODE cohort, along with genome-wide association study summary statistics for Addison’s disease comprising 1 223 cases and 4 097 controls from Sweden and Norway, were analyzed in a two-sample two-way MR framework. The primary causal inference was performed using inverse variance weighting, with MR-Egger regression, weighted median, and maximum likelihood methods employed as sensitivity analyses to assess the robustness of the findings. To mitigate reverse causality, MR analysis was conducted with Addison’s disease as the exposure factor and plasma proteins as the outcome variables. Results A total of 105 plasma protein closely associated with Addison’s disease were included in the forward study. Among them, sialic acid binding Ig like lectin 5, poly ADP-ribose polymerase, ectonucleotide pyrophosphatase/phosphodiesterase family member 5, butyrophilin subfamily 3 member A3, collagen type Ⅺ alpha 2 chain (COL11A2) and calsyntenin-1 still exhibited certain associations after multiple corrections (P<0.05). In the reverse study, only COL11A2 closely associated with Addison’s disease [odds ratio=0.98, 95% confidence interval (0.96, 1.00), P=0.026]. Conclusions This research discovers that sialic acid binding Ig like lectin 5, poly ADP-ribose polymerase, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 significantly enhance the risk of Addison’s disease, whereas butyrophilin subfamily 3 member A3, COL11A2, and calsyntenin-1 decrease the risk of Addison’s disease. Moreover, there is a potential reverse causal relationship between Addison’s disease and COL11A2.