The effect of fishmeal (FM) replacement with Spirulina (Arthrospira platensis) meal (SPM) was investigated in Asian seabass (Lates calcarifer) diet. Dietary FM was replaced with SPM at 5 (SP5%) and 10% (SP10%) and a diet without SPM served as the control group. One hundred and thirty five L. calcarifer juveniles (45.0 ± 0.2 g) were randomly distributed into nine 300-L circular polyethylene tanks (15 fish/tank). SP10% group had the highest final weight that was associated with better feed conversion ratio value. A higher gut amylase activity was observed in SPM-treated groups than the control group. SP5% group had a higher gut trypsin activity than other treatments. The liver superoxide dismutase activity in SP5% was higher than the other groups. The liver reduced glutathione level increased with increasing SPM level in the diets. The plasma lysozyme activity in SP10% group was higher than other groups. The plasma cholesterol and alkaline phosphatase contents decreased in the fish fed with SP5%. The plasma aspartate aminotransferase decreased in the fish fed with SPM-supplemented diets. Based on the above-mentioned findings, dietary FM replacement with SPM at 10% is recommended for growth and improving health status in L. calcarifer juveniles.