The beneficial effects of antioxidants have been investigated and reported for decades. These include (but are not limited to) the positive effects on the endocrine, reproductive, and central nervous systems. Free radicals, which have been known to be formed during many processes, including drug metabolism, and introduced as the main player in oxidative stress conditions, would be scavenged and neutralized by antioxidant agents. Whether endogenous or exogenous, they have been known to stand against many pathologies such as neurodegeneration, nephrotoxicity, inflammation, cancer, and aging, as well as pain and related challenges, namely, tolerance and dependence on analgesics. Despite the numerous reports of the benefits, the volume of studies focusing on the potential harms seems to be insufficient. It is important to note that some of the negative effects can be serious and challenging. In fact, the words "negative" or "positive" would be defined under a particular condition. Most likely, the most well-known example would be the challenges of antioxidant consumption in carcinogenesis, although many other conditions would be the focus. In this regard, the overuse of many antioxidant nutraceuticals, such as vitamin E, β-carotene, and lipoic acid, has been reported to be associated with serious complications. In this review, in addition to the bright side, we are going to scrutinize the controversies surrounding antioxidant administration.