This study investigated the environmental effects of two familiar emerging contaminants, sulfamethoxazole (SMX) and erythromycin (ERY), and their mixture (10:1 w/w) using a green microalga, R. subcapitata. The cell density, pigment content, and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST) were analyzed. The calculated EC50 values of SMX, ERY, and their mixture after 96 h were 0.49, 0.044, and 0.06 mg/L, respectively. High concentrations of antibiotics lead to a decrease in chlorophyll a and total carotenoid content, affecting the ability to photosynthesize ROS scavenging capacity. This may be a factor leading to the inhibition of algal growth. When R. subcapitata was exposed to SMX and the mixture, SOD and CAT increased to resist oxidative damage, while the activities of GSH and GST decreased, suggesting that this algae’s antioxidant system was unbalanced due to oxidative stress. R. subcapitata reduced the ERY-induced ROS by increasing the activities of SOD, GSH, and GST. The difference in the contents of nonenzymatic antioxidants and enzyme antioxidants in R. subcapitata indicated the antioxidant mechanisms to SMX and ERY were not identical. This study provides insights into the oxidative stress process in R. subcapitata under different antibiotics.