Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q, but affected individuals also exhibit intellectual disability and developmental delay. UBE3A, the gene encoding the ubiquitin protein ligase E3A, is likely a major driver of Dup15q because individuals with maternal, but not paternal 15q duplications have the disorder, and UBE3A is the only imprinted gene expressed solely from the maternal allele in mature neurons. Nevertheless, the exact role of UBE3A is yet to be determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, UBE3A expression was manipulated in patient-derived induced pluripotent stem cell (iPSC) lines using antisense oligonucleotides. Dup15q neurons exhibited hyperexcitability features compared to genome-edited isogenic control neurons, and this phenotype was generally prevented by normalizing UBE3A levels throughout in vitro development. Overexpression of UBE3A in an iPSC line with a paternal duplication resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes. However, the inability of UBE3A overexpression to recapitulate synaptic phenotypes suggests an important role for non-imprinted genes in the disorder.