There are limited published reports regarding the optimal dosage of spent mushroom. This study investigated the effect of various levels of spent mushroom derived from C. militaris as an alternative growth promoter to an in-feed antibiotic on the growth performance, blood profiles, immunoglobulin, inflammation, and microbial count of weaning pigs. A total of 120 pigs (6.63 ± 0.13 kg initial body weight) were blocked by weight and sex in a randomized complete block design. Each treatment had six replicates of four pigs each. The pigs were allotted into five treatments: (1) positive control (PC) with 150 mg/kg colistin; (2) negative control (NC) without antibiotic inclusion; and (3–5) negative control groups with 0.5, 1.0, and 1.5 g/kg of C. militariss pent mushroom (SM), respectively. Blood samples were collected at day 35 for determination of blood-related lipid metabolism and immunity. Fresh fecal samples were collected to examine microbial counts on day 35 postweaning. The results showed that SM at 1.5 g/kg improved the body weight, average daily weight gain, and average daily feed intake of weaning pigs in the overall period (p < 0.05). Moreover, the highest dosage of SM caused improvements in the concentrations of high-density lipoprotein, and immunoglobulin A, along with suppressions of total cholesterol, interleukin-1, tumor necrosis factor-α, and E. coli (p < 0.05). Therefore, the weaned pigs fed a 1.5 g/kg SM diet showed improved growth performance and displayed greater immunoglobulin secretion and lower inflammation, pathogenic population, and cholesterol concentration.