Introduction: Methotrexate (MTX), Moringa oleifera (MO), and Andrographis paniculata (AP) have been reported to have anti-hyperglycemic, antioxidative, and anti-inflammatory effects in diabetic rats. This study aims to investigate the single and combination effects of MTX, MO, and AP on random blood glucose levels, interleukin-6 (IL-6) levels, and trabecular density in diabetic rats. Methods: A total of 49 male rats were divided into seven groups, namely one control group and six diabetes mellitus (DM) groups. All rats in the DM groups were injected with streptozotocin-nicotinamide (STZ-NA) intraperitoneally. In addition, the DM groups were administered with a placebo daily (DG), a single dose of 500 mg/kg BW MO daily (DG+MO), a single dose of 500mg/kg BW AP daily (DG+AP), a single dose of 7 mg/kg BW MTX once a week (DG+MTX), a combination of MTX+MO, and a combination MTX+AP, respectively. The experiment lasted for 28 days. On day 29, the right and left femur of the rats were collected for IL-6 examination (ELISA) and histopathological analysis. Results: IL-6 expression levels were significantly lower in diabetic rats treated with single and combination of MTX, MO, and AP compared to untreated diabetic rats (p < 0.05). However, the random blood glucose levels and trabecular density between treated and untreated diabetic rats were not significantly different (p < 0.001, p = 0.152). In addition, IL-6 levels were not correlated with trabecular density in all groups (r = -0.057, p = 0.722). Conclusion: Single doses of MTX, MO leaf extract, and AP leaf extract could suppress IL-6 expression in the femur tissue in diabetic rats. However, the IL-6 expression was not correlated with trabecular density although it significantly affected blood glucose levels in this study.