Among plant protein sources, soy protein concentrate (SPC) has lower anti-nutritional factors and higher protein content. The aim of this study was to evaluate the effect of replacing fish meal in diet of rice field eel Monopterus albus with soy protein concentrate on growth performance, serum biochemical indices, intestinal digestive enzymes and growth-related genes expression in skeletal muscle. Six isonitrogen (45% crude protein) and isolipidic (5.5% crude lipid) diets were formulated with 0 g/kg, 8.5 g/kg, 17 g/kg, 25.5 g/kg, 34 g/kg and 42.5 g/kg SPC inclusion to replace 0%, 15%, 30%, 45%, 60% and 75% of fish meal (S0 (control), S8.5, S17, S25.5, S34, S42.5, respectively). Each diet was randomly assigned to triplicate groups of 100 fish per net cage (mean initial weight 25.56 ± 0.12 g). The fish were fed once at 18:00 per day for 56 days. Results showed that weight gain and feed intake significantly decreased in fish fed S42.5 (P < 0.05). Feed conversion rate was significantly higher in S34 and S42.5 groups compared to the other treatments (P < 0.05). No significant effects were found on hepatosomatic index and body composition among treatments. Viscerosomatic index significantly decreased with the increasing levels of SPC inclusion. Amylase and lipase activities in intestine peaked at S17 group. Dietary SPC supplementation significantly reduced the activities of intestine trypsin and serum glutamic oxalacetic transaminase and glutamate pyruvate transaminase as well as the content of serum triglyceride, total cholesterol, low density lipoprotein cholesterol and malondialdehyde, but significantly elevated the activities of catalase and total antioxidant capacity (P < 0.05). The superoxide dismutase activity had a rising trend compared to the control. High supplementation levels of dietary SPC down-regulated myogenic determination factor and myogenin mRNA expression, but up-regulated myostatin mRNA expression. These results suggested that fish meal could be partially replaced by SPC in diet of M. albus and the optimal supplementation level of SPC was 26% by using broken-line model curve. Replacing fish meal with dietary SPC has benefit in enhancing serum antioxidant capacity, improving serum lipid profile and modulating growth-related genes expression pattern in skeletal muscle of M. albus.