TAR DNA‐binding protein (TDP‐43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post‐translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We generated human cell lines expressing tagged forms of wild‐type and mutant TDP‐43 and observed that TDP‐43 controls its own expression through a negative feedback loop. The RNA‐binding properties of TDP‐43 are essential for the autoregulatory activity through binding to 3′ UTR sequences in its own mRNA. Our analysis indicated that the C‐terminal region of TDP‐43, which mediates TDP‐43–hnRNP interactions, is also required for self‐regulation. TDP‐43 binding to its 3′ UTR does not significantly change the pre‐mRNA splicing pattern but promotes RNA instability. Moreover, blocking exosome‐mediated degradation partially recovers TDP‐43 levels. Our findings demonstrate that cellular TDP‐43 levels are under tight control and it is likely that disease‐associated TDP‐43 aggregates disrupt TDP‐43 self‐regulation, thus contributing to pathogenesis.