Information and Communication Technology (ICT) integration is essential, especially after the COVID-19 pandemic. While the need for ICT integration in today’s pedagogical activities is inevitable, online instruction in Ghanaian higher education is still challenging. Referring to the pressing need for ICT integration and online instructions amid COVID-19, we assess the challenges academic staff in Ghanaian universities encounter concerning online instructions and ICT integration into pedagogical activities. We conducted a cross-sectional survey with 628 (response rate of 83.1%, N= 522) academic staff from two universities. Results reveal that instructors/lecturers’ challenges (inadequate ICT infrastructure and lack of stable electric power) and institutional challenges (lack of consistent practice and limited technical assistance) pre- dominantly affects online instructions and ICT integration. The implication drawn from our findings is that the challenges of online instruction and ICT integration in Ghanaian universities are interrelated. We recommend that stakeholders and policy-makers in Ghanaian universities should endeavour to provide holistic solutions rather than solving the identified challenges in isolation.