A comparative quantitative content analysis was adopted to explore the frames, tones, and information sources for the coverage of COVID-19 vaccines and vaccination in four countries in Africa. The news portals and countries for this study were purposively sampled based on the World Press Freedom Index released by Reporters Without Borders for 2021. Namibia, South Africa, Ghana, and Botswana are among the top ten countries in Africa with the best Media Freedoms. The findings showed that Ghana’s news portals’ coverage of COVID-19 vaccines and vaccination campaigns used mainly unofficial sources in the coverage of COVID-19 vaccines and vaccination stories, whereas Botswana, Namibia, and South African media used official sources. Other findings show that Ghana’s news portals covered COVID-19 vaccines and vaccination stories in a negative tone and employed conflict and economic consequence frames. Botswana, Namibia, and South African news portals, however, adopted neutral and positive tones and framed them according to human interest, responsibility, and morality. The results suggest that the text of the news articles from the four African countries’ coverage of the COVID-19 vaccines and vaccination adopted different generic framing styles, and the tones were predominantly a mixture of positive, neutral, and negative.