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Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness., Author Summary Two distinct families of interferons (IFNs), type I (IFN-α/β) and type III (IFN-λ) IFNs, are quickly produced in response to virus infection and engage distinct receptors to invoke shared rapid and broad-spectrum antiviral mechanisms against invading pathogens. However, the relative importance of type I and type III IFNs in protecting different organ systems against specific viruses or distinct strains of an individual virus remains to be fully explored. Here we demonstrated in suckling mice that neither type I nor type III IFNs are effective in blocking intestinal replication of murine rotavirus, rather, viral clearance is dependent upon adaptive immune responses. In contrast, both IFN types cooperate to control intestinal replication and extra-intestinal spread of simian rotavirus in neonatal mice. Unexpectedly, we found that although intestinal epithelial cells (IECs) respond to both types of IFNs in neonatal mice, responsiveness of IECs to type I IFNs, but not type III IFNs, is diminished in adult mice. Transcriptional analysis showed that both types of IFN receptors induced overlapping intestinal antiviral responses, which were abrogated only when both receptor types were deleted. Overall, these findings reveal a well-coordinated spatial and temporal regulation of antiviral defenses by type I and type III IFNs in the gastrointestinal tract that varies significantly depending on the viral strain examined.