The study investigated the effect of probiotics in combination with enteral nutrition in patients with severe acute pancreatitis. A prospective, randomized, double-blind study enrolled 130 patients who received either enteral nutrition with probiotics or placebo for 14 days. The probiotic group achieved a shorter period of relief from abdominal pain (4.21 ± 0.53 days vs. 5.85 ± 0.62 days) and shorter hospital stay (20.02 ± 2.14 days vs. 26.25 days). Probiotics led to greater reductions in inflammatory markers (endotoxin, diamine oxidase, CRP, TNF-α, and IL-6) and greater increases in immune markers (IgG, IgM, IgA) and nutritional markers (prealbumin, albumin, transferrin). In the group with probiotics, a higher number of beneficial bacteria (lactobacilli and bifidobacteria) and a lower number of harmful bacteria (enterobacteria and enterococci) were detected on the 7th and 14th day. Despite these positive findings, no differences were found in 28-day mortality, in-hospital mortality, or the number of patients with persistent organ failure.