The invention discloses a compound preparation capable of effectively improving the disease resistance of aquatic animals and a preparation method thereof. The compound preparation comprises the following components in parts by mass: 55-65 parts of microbial powder, 10-15 parts of astragalus polysaccharide, 10-15 parts of yeast cell walls, 5-10 parts of plant essential oil and 1-5 parts of vitaminB6. The coordination of the components is capable of reforming the intestinal flora structure, changing the proportion of unsaturated fatty acids in metabolic products of intestinal acid-producing bacteria, inhibiting enteric pathogenic bacteria and other harmful substances, restoring intestinal mucous membranes, promoting digestion and absorption of nutrients, simultaneously enabling animal bodies to have enhanced nonspecific immunity, enhanced stress resistance and stronger resistivity to viruses, pathogenic bacteria, parasites and polluted environments, comprehensively improving the utilization ratio of feed and survival rate of the animal bodies, reducing residual feed, purifying excrement and optimizing and normalizing an intensive culture mode.