Serious dinoflagellate blooms produce homoyessotoxin (homo-YTX) and ammonia (NH3-N) in eutrophic seawaters, posing threats to the healthy development of the mariculture industry. This study aimed to explore the toxicity mechanism of homo-YTX and NH3-N on the survival of abalone, which is important for the ecotoxicological research and cultivation of shellfish. The economy abalone Haliotis discus hannai was placed in homo-YTX (0, 2, 5, and 10 μg L−1) and NH3-N (0, 1.08, and 3.16 mg L−1) and a mixture of the two compounds to determine the survival rate (S), antioxidative responses, physiological activities, and apoptosis of abalone. Results show that the combination of homo-YTX and NH3-N increased the reactive oxygen species level, the malondialdehyde content, and the expression level of BCL2-associated X but decreased S; the activities of superoxide dismutase, catalase, adenosine triphosphatase, glutamic–pyruvic transaminase, xanthine oxidase, lactate dehydrogenase, and lysozyme; and the expression level of B-cell lymphoma-2. The activities of alkaline phosphatase and acid phosphatase in 10 μg L−1 of homo-YTX and 3.16 mg L−1 of NH3-N solutions and in the mixture of the two toxicants decreased. The caspase3 expression level was downregulated in 10 μg L−1 of homo-YTX. These results suggest that homo-YTX and NH3-N enhanced the oxidative stress and lipid peroxidation reactions, inhibited the energy supply, disrupted the metabolic and immune physiological functions, and activated apoptosis in the gills of abalone. ROS-mediated physiological activities and apoptosis were among the potential toxicity mechanisms of the interactive effects of homo-YTX and NH3-N on abalone.