We assessed the effects of a fishmeal (FM)‐ and two soya‐based diets [without or with prebiotic (GroBiotic® ‐A; GBA) supplementation] on the production performance, non‐specific immunity, blood parameters and gut microbiota diversity of red drum, Sciaenops ocellatus. All diets were formulated to contain 450 g/kg crude protein (CP) and 120 g/kg lipid. A combination of soya bean meal and soya protein concentrate (SP) was used to replace 88% of the FM in the FM‐based diet (REF) originating the first soya‐based diet (SOY). The second soya‐based diet (SOY + GBA) was designed identically to SOY except for the supplementation of GBA (20 g/kg) substituting for wheat flour. After feeding the experimental diets to triplicate groups of 25 (~3.4 g/fish) and 90 (~4.1 g/fish) red drum juveniles for 9 (Trial I) and 16 weeks (Trial II), our results showed that (i) red drum was highly sensitive to the soya‐based diets in the first week of feeding; (ii) replacing 88% of FM with SP reduced the production performance of red drum without affecting intestinal micromorphology; (iii) whole‐blood leucocyte oxidative radical production was unaffected while lower haematocrit and higher plasma lysozyme activity were found in fish fed REF; (iv) plasma osmolality was unaffected while lower glucose and higher lactate levels were observed in fish fed SOY and SOY + GBA; (v) 16S rRNA gene‐based diversity of fish gut microbiota was affected both by SP and by GBA. This study expands the information on red drum responses to soya‐based diets and prebiotic supplementation.