Histone proteins package DNA into nucleosomes, forming chromatin and thereby safeguarding genome integrity. Proper histone expression is essential for cell proliferation and chromatin organization, yet the upstream regulators of histone supply remain in-completely understood. PRMT5—a cell essential type II protein arginine methyltransferase frequently overexpressed in cancer—catalyzes symmetric dimethylation of arginine residues and is known to regulate transcription, splicing, and mRNA sub-cellular transit. Despite the pre-clinical development of PRMT5 inhibitors, its crucial molecular functions in proliferating cells remain unre-solved. Here, we combine temporal chemical inhibition, multi-omic profiling, and high-resolution imaging to define the immediate cellular consequences of PRMT5 loss. We find that PRMT5 activity is required to sustain histone gene transcription and histone protein production during S phase, and that its inhibition leads to rapid reduction of histone mRNA, reduced histone protein levels, and replication-associated stress, as indicated by micronuclei formation and cellular DNA loss. These findings establish PRMT5 as a critical regulator of histone homeostasis and reveal a previously unrecognized mechanism linking arginine methylation to chromatin integrity and genome stability.