Background and Objectives: Multiple evaluations of oxidative stress in individuals with substance use disorder show elevated levels compared to non-substance-abusing individuals. Information concerning antioxidant defense mechanisms in relation to alcohol and opioid dependence is variable and sometimes contradictory. The objective of the present investigation was to identify and compare several antioxidants in plasma during distinct phases of alcohol and opioid dependency (intoxication and withdrawal). Materials and Methods: This case study focuses on individuals with opioid and alcohol addiction. We recruited 80 participants (males aged 40 ± 10 years) and equally divided them into two categories: those with alcohol addiction and those with opioid addiction. A control group consisted of 20 healthy adults (males aged 35 ± 10 years). The spectrophotometric methods were used to quantify catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity in plasma. Antioxidant values were analyzed between groups using pairwise Mann–Whitney tests. Results: During withdrawal from alcohol and opioids, catalase activity tends to decrease compared to intoxication. The overall activity of superoxide dismutase exhibited an increase during alcohol intoxication and withdrawal and a reduction during opioid withdrawal compared to the intoxication phase. Both alcohol and opioids reduced plasma GPx activity in withdrawal cases, although the extent of this decrease varied considerably. Conclusions: The study confirms the valuable impact of addiction on the organism’s oxidative stress and reveals various behaviors of antioxidant defense enzymes during intoxication and withdrawal phases.