The degenerative muscle disorder facioscapulohumeral dystrophy (FSHD) is thought to be caused by the inappropriate expression of the Double Homeobox 4 (Dux4) protein in muscle cells leading to apoptosis. Expression of Dux4 in the major form of FSHD is a function of two contributing molecular changes: contractions in the D4Z4 microsatellite repeat region where Dux4 is located and an SNP present within a region downstream of the D4Z4. This SNP provides a functional, yet non-consensus polyadenylation signal (PAS) is used for the Dux4 mRNA 3' end processing. Surprisingly, the sequences flanking the Dux4 PAS do not resemble a typical cleavage and polyadenylation landscape with no recognizable downstream sequence element and a suboptimal cleavage site. Here, we conducted a systematic analysis of the cis-acting elements that govern Dux4 cleavage and polyadenylation. Using a transcriptional read-through reporter, we determined that sequences downstream of the SNP located within the β-satellite region are critical for Dux4 cleavage and polyadenylation. We also demonstrate the feasibility of using antisense oligonucleotides to target these sequences as a means to reduce Dux4 expression. Our results underscore the complexity of the region immediately downstream of the D4Z4 and uncover a previously unknown function for the β-satellite region in Dux4 cleavage and polyadenylation.