The COVID-19 pandemic and control measures adopted by countries globally can lead to stress and anxiety. Investigating the coping strategies to this unprecedented crisis is essential to guide mental health intervention and public health policy. This study examined how people are coping with the COVID-19 crisis in Ghana and identify factors influencing it. This study was part of a multinational online cross-sectional survey on Personal and Family Coping with COVID-19 in the Global South. The study population included adults, ≥18 years and residents in Ghana. Respondents were recruited through different platforms, including social media and phone calls. The questionnaire was composed of different psychometrically validated instruments with coping as the outcome variable measured on the ordinal scale with 3 levels, namely, Not well or worse, Neutral, and Well or better. An ordinal logistic regression model using proportional odds assumption was then applied. A total of 811 responses were included in the analysis with 45.2% describing their coping level as well/better, 42.4% as neither worse nor better and 12.4% as worse/not well. Many respondents (46.9%) were between 25-34 years, 50.1% were males while 79.2% lived in urban Ghana. Having pre-existing conditions increased the chances of not coping well (aOR = 1.86, 95%CI: 1.15-3.01). Not being concerned about supporting the family financially (aOR = 1.67, 95%CI: 1.06-2.68) or having the feeling that life is better during the pandemic (aOR = 2.37, 95%CI: 1.26-4.62) increased chances of coping well. Praying (aOR: 0.62, 95%CI: 0.43-0.90) or sleeping (aOR: 0.55, 95%CI: 0.34-0.89) more during the pandemic than before reduces coping. In Ghana, during the COVID-19 pandemic, financial security and optimism about the disease increase one's chances of coping well while having pre-existing medical conditions, praying and sleeping more during the pandemic than before reduces one's chances of coping well. These findings should be considered in planning mental health and public health intervention/policy.