Seaweeds, including the green Ulva lactuca, can potentially reduce competition between feed, food, and fuel. They can also contribute to the improved development of weaned piglets. However, their indigestible polysaccharides of the cell wall pose a challenge. This can be addressed through carbohydrase supplementation, such as the recombinant ulvan lyase. The objective of our study was to assess the muscle metabolism of weaned piglets fed with 7% U. lactuca and 0.01% ulvan lyase supplementation, using an integrated transcriptomics (RNA-seq) and proteomics (LC–MS) approach. Feeding piglets with seaweed and enzyme supplementation resulted in reduced macronutrient availability, leading to protein degradation through the proteasome (PSMD2), with resulting amino acids being utilized as an energy source (GOT2, IDH3B). Moreover, mineral element accumulation may have contributed to increased oxidative stress, evident from elevated levels of antioxidant proteins like catalase, as a response to maintaining tissue homeostasis. The upregulation of the gene AQP7, associated with the osmotic stress response, further supports these findings. Consequently, an increase in chaperone activity, including HSP90, was required to repair damaged proteins. Our results suggest that enzymatic supplementation may exacerbate the effects observed from feeding U. lactuca alone, potentially due to side effects of cell wall degradation during digestion.