The present study evaluated the interactive benefits of dietary administration of heat-killed Lactobacillus plantarum (LP) and vitamin C (VC) on the growth, oxidative status and immune response of red sea bream (Pagrus major). A diet without LP and VC supplements was employed as a control diet. Four other test diets with 0 or 1 g LP kg−1 combined with 0.5 or 1 g VC kg−1 (2 × 2 factorial design) were fed to red sea bream (2 ± 0.01 g) for 56 days. A significant interaction was found between LP and VC on final body weight (FNW), weight gain (WG), hematocrit (HCT), serum bactericidal (BA) and lysozyme (LZY) activities, mucus LZY and peroxidase (PA) activities, nitro blue tetrazolium (NBT), catalase, mucus secretion and tolerance against low salinity stress test (LT50) (P < 0.05). In addition, FNW, WG, specific growth rate, feed and protein efficiency ratio, serum (BA, LZY, PA and NBT), mucus (LZY and PA), superoxide dismutase, malondialdehyde and mucus secretion were significantly affected by either LP or VC (P < 0.05). Furthermore, only LP was a significant factor on survival, plasma total cholesterol, mucus BA and alternative complement pathway (P < 0.05). However, VC supplementation affected on HCT and LT50. Interestingly, fish fed with both LP at 1 g kg−1 diet with VC at 0.5 or 1 g kg−1 diet showed higher growth, humoral and mucosal immune responses, anti-oxidative status, mucus secretion and LT50 as well as decreased plasma, triglyceride and total cholesterol levels than the fish fed control diet (P < 0.05). These results demonstrated that dietary LP and VC had a significant interaction for red sea bream with the capability of improving growth performance and enhancing stress resistance by immunomodulation.