Angelman syndrome (AS) is a severe neurodevelopmental disorder associated with disruption of maternally inherited UBE3A (ubiquitin protein ligase E3A) expression. At the present time, there is no effective treatment for AS. Mouse lines with loss of maternal Ube3a (Ube3am–/p+) recapitulate multiple aspects of the clinical AS profile, including impaired motor coordination, learning deficits, and seizures. Thus, these genetic mouse models could serve as behavioral screens for preclinical efficacy testing, a critical component of drug discovery for AS intervention. However, the severity and consistency of abnormal phenotypes reported in Ube3am–/p+ mice can vary, dependent upon age and background strain, which is problematic for the detection of beneficial drug effects. As part of an ongoing AS drug discovery initiative, we characterized Ube3am–/p+ mice on either a 129S7/SvEvBrd-Hprtb-m2 (129) or C57BL/6J (B6) background across a range of functional domains and ages to identify reproducible and sufficiently large phenotypes suitable for screening therapeutic compounds. The results from the study showed that Ube3am–/p+ mice have significant deficits in acquisition and reversal learning in the Morris water maze. The findings also demonstrated that Ube3am–/p+ mice exhibit motor impairment in a rotarod task, hypoactivity, reduced rearing and marble-burying, and deficient fear conditioning. Overall, these profiles of abnormal phenotypes can provide behavioral targets for evaluating effects of novel therapeutic strategies relevant to AS.