Mitochondrial oxidative damage is related to diverse pathologies, including cancer and neurodegenerative diseases. Shielding mitochondria from oxidative damage with mitochondriotropic antioxidants is by now considered an effective therapeutic strategy. Despite the success of the approach, some concerns related with cytotoxicity have been reported. For instance, AntiOxCIN6 is a mitochondriotropic antioxidant based on caffeic acid (CAF) that is cytotoxic in hepatocarcinoma (HepG2) cell lines. PEGylation, often used to enhance drug pharmacologic and pharmaceutical properties, was herein applied to modulate AntiOxCIN6 toxicity drawbacks. So, a dual-functionalization of polyethylene glycol (PEG) with TPP+ and CAF as targeting and antioxidant arms, respectively, was performed by a two-step amidation strategy using ethyl chloroformate and EDC/NHS as coupling reagents. The data showed that the antioxidant properties related with CAF moiety were maintained in the CAF-PEG-TPP conjugate (CPTPP) and that PEGylation process reverted the loss of ability to chelate iron observed with AntiOxCIN6.. In cellular studies, CPTPP was nontoxic to human HepG2 and neuronal (SH-SY5Y) cells, while both CAF and AntiOxCIN6 demonstrated harmful effects in the same cell lines. The lack of cytotoxic events linked to oxidative stress levels observed with CPTPP suggested that PEGylation process somehow modulates the putative toxicity related with the presence of a catechol moiety and/or the TPP+ cation. In addition, the mitochondrial oxygen consumption was not significantly affected by CPTPP treatment in SH-SY5Y cells when compared with nontreated cells. CPTPP showed remarkable antioxidant effects in cell-based assays against several oxidative stress-induced agents (H2O2, t-BHP, and FeNTA). From the data it can be concluded that PEGylation technology can modulate the toxicity of mitochondriotropic antioxidants without disturbing the antioxidant profile of the core antioxidant. PEGylation can be considered a relevant tool to hasten the difficulties related to the design and development of mitochondrial nontoxic and operative drug candidates.