The synthesis of highly diverse libraries has become of paramount importance for obtaining novel leads for drug and agrochemical discovery. Herein, the step-economical diversity-oriented synthesis of a library of various pyrimidine–N-heterocycle hybrids was developed, in which a 4,6-dimethoxypyrimidine core was incorporated into nine kinds of N-heterocycles. A total of 34 structurally diverse compounds were synthesized via a two-step process from very simple and commercially available starting materials. Further, in vivo biological screening of this library identified 11 active compounds that exhibited good post-emergence herbicidal activity against D. sanguinalis at 750 g ai per ha. More importantly, pyrimidine–tetrahydrocarbazole hybrid 5q showed good to excellent herbicidal activity against five test weeds at the same dosage. Pyrimidine–tetrahydrocarbazole hybrids represent a novel class of herbicidal agents that may become promising lead compounds in the herbicidal discovery process.