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Lately, <i>Spirulina platensis</i> (SP), as an antioxidant, has exhibited high potency in the treatment of oxidative stress, diabetes, immune disorder, inflammatory stress, and bacterial and viral-related diseases. This study investigated the possible protective role of <i>Spirulina platensis</i> against ARV-induced oxidative stress in HepG2 cells. Human liver (HepG2) cells were treated with ARVs ((Lamivudine (3TC): 1.51 µg/mL, tenofovir disoproxil fumarate (TDF): 0.3 µg/mL and Emtricitabine (FTC): 1.8 µg/mL)) for 96 h and thereafter treated with 1.5 µg/mL <i>Spirulina platensis</i> for 24 h. After the treatments, the gene and protein expressions of the antioxidant response pathway were determined using a quantitative polymerase chain reaction (qPCR) and Western blots. The results show that <i>Spirulina platensis</i> decreased the gene expressions of <i>Akt</i> (<i>p</i> < 0.0001) and <i>eNOS</i> (↓<i>p</i> < 0.0001) while, on the contrary, it increased the transcript levels of <i>NRF-2</i> (↑<i>p</i> = 0.0021), <i>Keap1</i> (↑<i>p</i> = 0.0002), <i>CAT</i> (↑<i>p</i> < 0.0001), and <i>NQO-1</i> (↑<i>p</i> = 0.1432) in the HepG2 cells. Furthermore, the results show that <i>Spirulina platensis</i> also decreased the protein expressions of NRF-2 (↓<i>p</i> = 0.1226) and pNRF-2 (↓<i>p</i> = 0.0203). Interestingly, HAART-SP induced an NRF-2 pathway response through upregulating NRF-2 (except for FTC-SP) (↑<i>p</i> < 0.0001), <i>CAT</i> (↑<i>p</i> < 0.0001), and <i>NQO-1</i> (except for FTC-SP) (↑<i>p</i> < 0.0001) mRNA expression. In addition, NRF-2 (↑<i>p</i> = 0.0085) and pNRF-2 (↑<i>p</i> < 0.0001) protein expression was upregulated in the HepG2 cells post-exposure to HAART-SP. The results, therefore, allude to the fact that <i>Spirulina platensis</i> has the potential to mitigate HAART-adverse drug reactions (HAART toxicity) through the activation of antioxidant response in HepG2 cells. We hereby recommend further studies on <i>Spirulina platensis</i> and HAART synergy.