Developing a sustainable feed with minimal or no fishmeal in tilapia production is a challenge to this industry. New Technology Promoter Binder (NTPB), a guanidinoacetic acid, is a nutritional supplement to enhance the energy metabolism of the muscle and brain tissue of vertebrates. This study aimed to evaluate several plant-based diet formulations with zero and minimal use of fishmeal enriched with NTPB on the growth, feed efficiency, and health status of Tilapia sp. The experimental diets in this study were conducted based on four formulations (minimum fishmeal/FM and zero fishmeal/NFM-based diets) with 0, 0.6, and 1.2 mg·kg−1 feed of NTPB supplementation. The research indicated that the various diets given to tilapia affected the growth performance of fish in terms of growth parameters and feed efficiency. Tilapias fed with NTPB grew better than those without NPTB in both FM- and NFM-based diets. The addition of NTPB was safe for tilapia as demonstrated in the blood glucose, urea, and creatinine levels, which were normal for healthy fish. The viscerosomatic and hepatosomatic indexes of tilapia fed with the experimental diets showed no distinct differences. Adding NTPB to tilapia diets increased the hardness and amino acid contents of the tilapia’s muscle, which would benefit consumers.