This study aimed to determine the effect of dexamethasone in combination with low-dose or high-dose daptomycin for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis. Efficacy (ΔCFU/mL) and cerebrospinal fluid (CSF) levels of daptomycin at 15 mg/kg and 25 mg/kg were studied in a rabbit model of pneumococcal meningitis, comparing them with the same doses in combination with dexamethasone at 0.125 mg/kg every 12 h over a 26-h period against two different Streptococcus pneumoniae strains, HUB 2349 and ATCC 51916 with daptomycin minimum inhibitory concentrations (MICs) of 0.09 mg/L and 0.19 mg/L, respectively. Daptomycin levels in CSF were lower when dexamethasone was given concurrently. Against strain HUB 2349, therapeutic failure occurred with daptomycin 15 mg/kg + dexamethasone; daptomycin 25 mg/kg + dexamethasone was better at reducing bacterial counts than the lower dose throughout treatment. Against the highly cephalosporin-resistant ATCC 51916 strain, daptomycin 15 mg/kg + dexamethasone achieved a lower bacterial decrease than daptomycin 15 mg/kg alone, and therapeutic failure at 24 h occurred in the daptomycin 15 mg/kg + dexamethasone group. Addition of dexamethasone to a 25 mg/kg daptomycin dose did not affect the efficacy of daptomycin: it remained bactericidal throughout treatment. In conclusion, against the studied strains, low-dose (15 mg/kg/day) daptomycin is affected by concomitant use of dexamethasone: CSF levels are reduced and its bacterial efficacy is affected. At a higher daptomycin dose (25 mg/kg/day), however, the use of dexamethasone does not alter efficacy; the combination appears to be a good choice for the treatment of pneumococcal meningitis.