Superoxide dismutase-rich () is derived from marine microalgae and has been reported to increase gene expression of nuclear factor erythroid 2-related factor 2 (NRF2) and related antioxidant enzymes in myoblast tissue culture models. Human research has indicated that supplementation can improve recovery from exercise-induced muscle damage, but its effects on endurance exercise performance and the molecular bases that may underlie any ergogenic effects are unclear. Healthy participants underwent 14 days of supplementation with 25 mg·day and placebo in a randomized, double-blind, crossover experimental design. Prior to and following each supplementation period, participants completed a high-intensity cycling test to assess time to exhaustion and peak oxygen uptake (V˙O2peak). A resting skeletal muscle biopsy was collected after both supplementation periods to assess gene expression changes. Compared to pre-supplementation values, V˙O2peak was increased following ( = 0.013) but not placebo ( = 0.66). Fold-change in glutathione peroxidase 7 [() 1.26 ± 1.37], glutathione-disulfide reductase [() 1.22 ± 1.41], glutathione S-transferase Mu 3 [() 1.34 ± 1.49], peroxiredoxin 6 [() 1.36 ± 1.57], extracellular signal-regulated kinase 3 [() 1.92 ± 2.42], (1.62 ± 2.16), p38 alpha [() 1.33 ± 1.58] and sirtuin 1 [() 1.73 ± 2.25] gene expression were higher after compared to placebo supplementation ( < 0.05). Short-term supplementation increased V˙O2peak and skeletal muscle gene expression of key enzymatic antioxidants (, , , and ), signalling kinases ( and ), post-translational regulators (), and transcription factors () that may protect against cellular stress insults.