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Orthoflaviviruses are enveloped, positive-sense RNA viruses comprising numerous human pathogens transmitted by hematophagous arthropods, which includes viruses such as dengue virus, Zika virus, and yellow fever virus. The nonstructural viral protein NS1 plays a pivotal role in the pathogenesis and life cycle of these viruses, functioning in two distinct forms: membrane-associated (mNS1) or secreted (sNS1). The versatility of NS1 is evident in its ability to modulate various aspects of the infectious process, from immune evasion to pathogenesis. As an intracellular protein, it disrupts many processes, interfering with signaling pathways and facilitating viral replication alongside other viral proteins. As a secreted protein, NS1 actively participates in immune evasion, interfering with the host’s immune system, inhibiting the complement system, facilitating viral dissemination, and disrupting endothelial barrier integrity. This review primarily aims to address the role of NS1 in viral pathogenesis associated with orthoflaviviruses.