Influenza B viruses are important human pathogens that remain inadequately studied, largely because available animal models are poorly defined. Here, we developed an immunocompromised murine models for influenza B virus infection, which we subsequently used to study pathogenicity and to examine antiviral efficacy of the neuraminidase inhibitor peramivir. We studied three influenza B viruses that represent both the Yamagata (B/Massachusetts/2/2012 and B/Phuket/3073/2013) and Victoria (B/Brisbane/60/2008, BR/08) lineages. BR/08 was the most pathogenic in genetically modified immunocompromised mice [BALB scid and non-obese diabetic (NOD) scid strains] causing lethal infection without prior adaptation. The immunocompromised mice demonstrated prolonged virus shedding with modest induction of immune responses compared to BALB/c. Rather than severe virus burden, BR/08 virus-associated disease severity correlated with extensive virus spread and severe pulmonary pathology, stronger and persistent natural killer cell responses, and the extended induction of pro-inflammatory cytokines and chemokines. In contrast to a single-dose treatment (75 mg/kg/day), repeated doses of peramivir rescued BALB scid mice from lethal challenge with BR/08, but did not result in complete virus clearance. In summary, we have established immunocompromised murine models for influenza B virus infection that will facilitate evaluations of the efficacy of currently available and investigational anti-influenza drugs.