(1) Background: This study investigated the effects of fermented palm kernel cake (FPKC) on growth performance, serum indices, rumen fermentation and microbiota in growing–fattening beef cattle. (2) Methods: Forty-eight Angus cattle (504.50 ± 52.45 kg) were randomly divided into four groups (n = 12). The control group was fed a basal diet, while treatment groups were fed diets with 10%, 20% and 30% FPKC replacing corn and soybean meal concentrate. The experiment included a 14-day adaptation period and a 56-day formal experimental phase. (3) Results: Compared with the control, 20% FPKC significantly increased average daily gain and decreased the feed-to-gain ratio (p < 0.05). All FPKC groups had lower serum alanine aminotransferase (ALT) (p < 0.05). The 20% and 30% FPKC groups showed higher IgA and T-AOC, and lower MDA (p < 0.05) and highly significantly lower IL-1β. All FPKC groups had higher ruminal propionic acid (p < 0.05). In particular, 20% FPKC modified rumen microbial structure and increased the relative abundance of Succinivibrionaceae_UCG-002 (p < 0.05). (4) Conclusions: Replacing part of concentrate with 20% FPKC (9.1% inclusion in the total diet) improved growth performance, enhanced immune and antioxidant function in growing–fattening beef cattle, optimized rumen fermentation, and increased the relative abundance of beneficial bacteria including Succinivibrionaceae_UCG-002.