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U.S. home healthcare agencies provide essential care to homebound patients, primarily older adults at high risk for infection. The COVID-19 pandemic intensified existing infection prevention and control challenges, particularly among marginalized communities. This qualitative study explored unique infection prevention and control challenges faced by agencies and differences in responses among those serving vulnerable populations. Ten agencies representing diverse geographic regions, ownership models, and patient characteristics participated; 25 staff across varied roles completed semi-structured interviews examining infection prevention and control policies, care coordination, and patient/caregiver communication during COVID-19. Thematic analysis identified four major themes: Into the Fray; Changing Relationships to Patients; Solutions Aimed at Care Provision Continuity; and Alleviating Fear and Providing Information. Staff experienced fear and stress from uncertainty and essential worker pressures, with urban infection prevention, quality, and education personnel particularly affected. Urban staff faced parking challenges and exposure risks in multi-generational homes; many rural staff contended with long drives and regional/county protocols that complicated patient access. Wearing full PPE in inclement weather further strained staff. Patient/caregiver hesitancy made trust building essential. Telehealth, education, remote work, and local partnerships supported care continuity, with corporately resourced agencies adapting more rapidly. Findings highlight the need for centralized guidance, telehealth investment, and stronger staff well-being supports in future public health crises.