The invention discloses a self-setting composition serving as a plugging agent. The self-setting composition is prepared from a hydroxyl compound, organic acid and an isocyanate-group compound. When the composition is injected into a portion (such as a well wall macropore or thick oil channel) needing to be plugged, the composition is self-set to be hardened at formation pressure and temperature to achieve the plugging purpose (for example, a macropore leakage zone or a thick oil contamination channel is plugged, or a thick oil layer near the well wall is isolated), therefore, a drilling fluid leakage channel or a thick oil contamination source is cut off, the problem that drilling fluid leaks or thick oil contaminates the drilling fluid is thoroughly solved, and it is guaranteed that drilling operation is successfully conducted.