While negative impacts of COVID-19-related remote instruction on children continue to emerge, it appears that vulnerable students will disproportionately bear the burden. One such vulnerable population is children being raised by grandparents. The purpose of this mixed methods study was to gain insight into custodial grandmothers’ (CGMs) experiences of their grandchildren’s remote instruction, as well as individual and contextual factors associated with these experiences. A national sample of 315 CGMs, drawn from two randomized clinical trials, completed an online survey in Spring of 2020. Results of a thematic analysis and supplemental quantitative analyses revealed three themes. First, access to technology and instructional supports were critical to the success of remote instruction, with barriers being difficulties using technology and poor-quality remote instruction. Next, grandchild socioemotional difficulties, and fit with remote instruction, were central to their engagement and success with remote instruction. Finally, CGMs experienced multiple stressors related to managing the demands of remote instruction, work, and family. Challenges associated with remote instruction were related to pre-pandemic difficulties such as grandchild problems and CGM depressive symptoms. Collectively, the results highlight how multiple adversities may have amplified grandchildren’s existing vulnerability to negative outcomes. Implications are addressed, including strategies for supporting children raised by grandparents beyond the COVID-19 pandemic.