Whether gingival crevicular fluid (GCF) indexes in patients with severe periodontitis affect the efficacy of drug treatment was a new direction of recent research. At present, there were few studies on the effects of inflammatory indicators, BGP, and MMP-8 levels in GCF on the efficacy of drug treatment in such patients. So the purpose of this study was to observe the changes in osteocalcin (BGP), matrix metalloproteinase-8 (MMP-8), and inflammatory indexes levels in GCF of patients with severe periodontitis. The correlation between the above indexes and the effect of drug treatment in the patients was analyzed, in order to provide guidance for improving the clinical curative effect of severe periodontitis. A retrospective analysis was conducted to collect the baseline data of patients with severe periodontitis who were treated with Minocycline Hydrochloride Ointment in our hospital. The inflammatory indicators, BGP, and MMP-8 levels in GCF were analyzed before drug treatment, and the treatment effect on the patients was counted. Logistic regression was used to analyze the correlation between BGP, MMP-8, and inflammatory indicators levels in GCF and the drug treatment effect on the patients. After statistical analysis, we found that the response rate was 69% and the inefficiency was 31%. There were no significant differences in C-reactive protein (CRP) and tumor necrosis factor- α (TNF- α ) levels between the inefficacy group and efficacy group ( P > 0.05). Compared with the efficacy group, the levels of interleukin-6 (IL-6), interleukin-1 β (IL-1 β ), interleukin-8 (IL-8), BGP, and MMP-8 were increased in the inefficacy group. High levels of IL-6, IL-1 β , IL-8, BGP, and MMP-8 were associated with ineffective drug treatment in patients with severe periodontitis (all OR >1 and P < 0.05). Levels of IL-6, IL-1 β , IL-8, BGP, and MMP-8 predicted that the AUCs of drug treatment failure in patients with severe periodontitis were all greater than 0.7, which were 1.398, 1.458, 1.244, 1.012, and 1.012, respectively. From this, we can conclude that increased levels of BGP, MMP-8, and inflammatory indicators such as IL-6, IL-1 β, and IL-8 in GCF would increase the risk of ineffective drug treatment in patients with severe periodontitis. The clinical treatment plan could be adjusted according to the levels of the above indicators in GCF to improve the effectiveness of drug treatment in patients.