The WHO has declared tuberculosis (TB) a global health emergency. Therefore, there is an urgent need to discover and develop new anti–TB drugs. Here we report on a new category of 5–substituted pyrimidine nucleosides as potent inhibitors of Myco–bacterium tuberculosis growth in vitro. A series of 2ʹ–deoxy–, 3ʹ–azido–2ʹ,3ʹ–dideoxy–, and 3ʹ–amino–2ʹ,3ʹ–dideoxypyrimidine nucleoside analogues bearing lengthy flexible alkyloxymethyl substituents exhibited marked inhibitory activity against M. tuberculosis in vitro. 5–Dodecyloxymethyl–2ʹ–deoxyuridine was found to be a potent inhibitor of M. tuberculosis propagation in vitro. In contrast, monophosphates of the tested nucleosides were devoid of antimycobacterial activity. This new class of inhibitors seems to be a promising chemotherapeutic agent against TB and merits further studies.