The effects of glucose effectiveness, the insulin-independent mechanism of glucose disposal, on hypoglycemia have not yet been fully investigated. Herein, in 50 males without a diagnosis of diabetes mellitus (median age 54 years, body mass index (BMI) ≥ 25), the index of glucose effectiveness (SgIo) was determined by a 75 g oral glucose tolerance test (OGTT), and continuous glucose monitoring (CGM) was performed for 6 days. The minimal glucose levels and the percentages of time below 70 mg/dL (3.9 mmol/L) (TBR70) during CGM were significantly associated with the SgIo tertile category in a biphasic manner. When TBR70 within 24 h after OGTT ≥ 0.6% was defined as subclinical reactive hypoglycemia (SRH), odds ratios of having SRH in SgIo tertile 1 (lowest) and tertile 3 (highest) compared to SgIo tertile 2 (middle) were both 11.7 (p = 0.007), while the odds ratios of the highest post-load insulin quartile were 22.9 (p = 0.001) and 1.07 (p = 0.742), respectively. The chances of having self-reported snacking habits, obesity (BMI ≥ 30), and impaired glucose tolerance were significantly higher in participants in SgIo tertile 1 compared to those in SgIo tertile 2, with odds ratios of 10.7 (p = 0.005), 11.2 (p = 0.02), and 13.8 (p = 0.002), respectively. However, there was no significant difference between SgIo tertile categories 2 and 3. In conclusion, SgIo is associated with SRH in a biphasic manner. In people with lower glucose effectiveness, the SRH-induced increase in appetite may create a vicious cycle that leads to obesity.