This study aimed to screen and optimize the liquid fermentation medium for a compound Chinese herbal matrix (comprising Astragalus membranaceus, Atractylodes macrocephala, Taraxacum mongolicum, and Glycyrrhiza uralensis) using Pleurotus ostreatus strain HXS-M1, with the ultimate goal of enhancing the bioavailability and efficacy of herbal active compounds through microbial fermentation. Carboxymethyl cellulase (CMCase) activity was used as the response indicator. A single-factor test was conducted to preliminarily screen suitable medium components, followed by a Box–Behnken design-based response surface methodology to establish a mathematical model for optimization. The results identified the optimal medium composition as follows: 43.0% compound Chinese herbal extract (as carbon source), 1.0% mung bean powder (as nitrogen source), and 0.1% calcium carbonate (as inorganic salt). Under these conditions, the maximum CMCase activity reached 39.92 U/mL. This optimized fermentation process not only improves enzyme yield but also promotes the degradation of herbal cell walls, facilitating the release of bioactive compounds, thereby enhancing pharmacological efficacy and supporting the development of antibiotic-free feed additives. The findings provide a technical foundation for further scaling up the fermentation process of Chinese herbs using P. ostreatus HXS-M1.