A 56-day culture experiment was conducted to assess the effects of lysophospholipid added to a low-fishmeal diet on growth performance, hepatopancreas health, and intestinal microbiome of Litopenaeus vannamei. Three experimental diets were set up in this study: normal fishmeal positive control diet (20% fishmeal, P), low fishmeal negative control diet (12% fishmeal, N), and low fishmeal + lysophospholipid diet (12% fishmeal with 0.1% lysophospholipid, L). The obtained results proved that L. vannamei fed the group N diet could inhibit growth performance (final body weight, weight gain, and specific growth rate), decrease whole-body crude protein, and inhibit hepatosomatic antioxidant capacity and digestive capacity. These adverse effects were significantly alleviated in group L. Compared with group P, the expression of hepatopancreas lipid metabolism genes and the triglyceride content were both increased in group N. The triglyceride level of group L was significantly higher than that of group P but lower than group N. Histological analysis showed that the addition of lysophospholipid could maintain the normal morphology of hepatopancreas and reduce pathological changes such as cell melanosis caused by a low fishmeal diet. In addition, the proportion of dominant colonizers of intestinal flora was unbalanced in group N. In group L, the imbalance was alleviated. In conclusion, the supplementation of lysophospholipid in the low-fishmeal diet of L. vannamei improved the weight gain, antioxidant capacity, digestive capacity of hepatopancreas, regulate hepatopancreas lipid metabolism and maintain healthy tissue morphology, and also regulate the intestinal flora structure.