Cd contamination in cacao beans is one of the major problems faced by cocoa producing countries in Latin America. Cacao scion-rootstock combinations influence the Cd accumulation in the shoot of the plant. The objective of this work was to carry out a comparative analysis between cacao scion rootstock combinations (CCN 51/BN 34, CCN 51/PS 13.19, CCN 51/PH 16 and CCN 51/CCN 51), contrasting for tolerance to cadmium (Cd) toxicity, by means of leaf proteomic profiles, in order to elucidate molecular mechanisms involved in tolerance to Cd toxicity. Cacao scion-rootstock combinations were grown in soil with 150 mg Cd kg−1 soil, together with the control treatment. Leaf samples were collected 96 h after treatments were applied. There were alterations in the leaf proteome of the cacao scion-rootstock combinations, whose molecular responses to Cd toxicity varied depending on the combination. Leaf proteomic analyzes provided important information regarding the molecular mechanisms involved in the tolerance and intolerance of cacao scion-rootstock combinations to Cd toxicity. Enzymatic and non-enzymatic antioxidant systems, efficient for eliminating ROS, especially the expressions of APX and SOD, in addition to the increase in the abundance of metalloproteins, such as ferredoxins, rubredoxin, ALMT, Trx-1 and ABC-transporter were key mechanisms used in the Cd detoxification in cacao scion-rootstock combinations tolerant to Cd toxicity. Carboxylic acid metabolism, glucose activation and signal transduction were also important processes in the responses of cacao scion-rootstock combinations to Cd toxicity. The results confirmed CCN 51/BN 34 as a cacao scion-rootstock combination efficient in tolerance to Cd toxicity.