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Night-shift work and sleep disorders are associated with type 2 diabetes (T2DM), and circadian rhythm disruption is intrinsically involved. Studies have identified several signaling pathways that separately link two melatonin receptors (MT₁ and MT₂) to insulin secretion and T2DM occurrence, but a comprehensive explanation of the molecular mechanism to elucidate the association between these receptors to T2DM, reasonably and precisely, has been lacking. This review thoroughly explicates the signaling system, which consists of four important pathways, linking melatonin receptors MT₁ or MT₂ to insulin secretion. Then, the association of the circadian rhythm with <i>MTNR1B</i> transcription is extensively expounded. Finally, a concrete molecular and evolutionary mechanism underlying the macroscopic association between the circadian rhythm and T2DM is established. This review provides new insights into the pathology, treatment, and prevention of T2DM.