Dried longan, dried goji, and dried jujube were used as raw materials to develop a nutritional meal replacement powder that could regulate the intestinal flora. The process of crushing these raw materials was optimized and evaluated using an orthogonal experimental design. Other nutritional ingredients were added using a mixture design. Next, fluidity, stability, and sensory scores were used as testing indicators to determine the optimal formulation of the longan-goji-jujube nutritional meal replacement powder. In addition, the effect of the nutritional meal replacement powder on the intestinal flora was evaluated. The results showed that the optimal processing of the compound fruit powder was as follows: using whey protein as a supplemental material, the mass ratio of raw material to supplemental material was 1:1.5, and the freezing ultrafine grinding time was 150 s. The ratio of the 3 raw materials was dried longan: dried goji: dried jujube=3.59:4.60:1. The nutritional meal replaement powder was developed based on the proportion of the mixture design. The optimal proportion of longan-goji-jujube nutritional meal replacement powder was determined using a mixture design as follows: 50% compound fruit powder, 5% whole milk powder, 5% plant fat powder, 10% puffed rice powder, and 30% maltodextrin powder. The obtained longan-goji-jujube nutritional meal replacement powder showed good stability, sensory scores, and nutritional balance. The longan-goji-jujube nutritional meal replacement powder significantly promoted the growth of members from Lactobacillus, Bifidobacterium, and Bacteroides and Akkermansia muciniphila, as well as the production of short-chain fatty acids, particularly acetic acid and butyric acid. Thus, the longan-goji-jujube nutritional meal replacement powder showed regulatory effects on the intestinal microbiota in vitro.