The red claw crayfish (Cherax quadricarinatus) is an economically important freshwater crustacean. This study comprehensively compared the physiological profiles of crayfish cultured in recirculating aquaculture systems (RAS) and rice–red claw crayfish co-culture systems (RRCS) over a 92-day experimental period (3 replicates per system; n = 15 crayfish sampled per group), focusing on growth performance, muscle quality, hepatopancreatic metabolomics, and intestinal microbiota. Results demonstrated that while RAS provided a significant growth advantage, RRCS exhibited superior muscle quality characterized by higher protein, lower moisture, and firmer texture. Regarding intestinal microecology, RAS induced a microbial shift toward the potentially pathogenic genus Vibrio, whereas RRCS promoted core symbionts like Candidatus Hepatoplasma. Multi-omics integration revealed that RRCS altered the intestinal microbiota and was associated with up-regulated hepatopancreatic pantothenate biosynthesis and TCA cycle pathways, alongside LysoPC-mediated membrane lipid remodeling. In conclusion, while RAS promotes rapid somatic growth, RRCS fosters a distinct intestinal microecology and hepatopancreatic metabolic profile that aligns with enhanced muscle quality. These findings provide a theoretical foundation for optimizing ecological aquaculture models.