BACKGROUND: Genomic surveillance of SARS-CoV-2 is crucial for monitoring the spread of COVID-19 and guiding public health decisions, but the capacity for SARS-CoV-2 testing and sequencing in Africa is low. We integrated SARS-CoV-2 surveillance into an existing influenza surveillance network with the aim of providing insights into SARS-CoV-2 transmission and genomics in Ghana. METHODS: In this molecular epidemiological analysis, which is part of a wider multifaceted prospective observational study, we collected national SARS-CoV-2 test data from 35 sites across 16 regions in Ghana from Sept 1, 2020, to Nov 30, 2021, via the Ghanaian integrated influenza and SARS-CoV-2 surveillance network. SARS-CoV-2-positive samples collected through this integrated national influenza surveillance network and from international travellers arriving in Accra were sequenced with Oxford Nanopore Technology sequencing and the ARTIC tiled amplicon method. The sequence lineages were typed with pangolin and the phylogenetic analysis was conducted with IQ-Tree2 and TreeTime. FINDINGS: During the study period, 5495 samples were submitted for diagnostic testing through the national influenza surveillance network (2121 [46·1%] of 4021 samples with complete demographic data were from female individuals and 2479 [53·9%] of 4021 samples were from male individuals). We also obtained 2289 samples from travellers who arrived in Accra and had a positive lateral flow test, of whom 1626 (71·0%, 95% CI 69·1-72·9) were confirmed to be SARS-CoV-2 positive. Co-circulation of influenza and SARS-CoV-2 in Ghana was detected, with increased cases of influenza in November, 2020, November, 2021, and January and June, 2021. In 4124 samples from individuals with influenza-like illness, SARS-CoV-2 was identified in 583 (14·1%, 95% CI 13·1-15·2) samples and influenza in 356 (8·6%, 7·8-9·5). Conversely, in 476 samples from individuals with of severe acute respiratory illness, SARS-CoV-2 was detected in 58 (12·2%, 9·5-15·5) samples and influenza in 95 (19·9%, 16·5-23·9). We detected four waves of SARS-CoV-2 infections in Ghana; each wave was driven by a different variant: B.1 and B.1.1 were the most prevalent lineages in wave 1, alpha (B.1.1.7) was responsible for wave 2, delta (B.1.617.2) and its sublineages (closely related to delta genomes from India) were responsible for wave 3, and omicron variants were responsible for wave 4. We detected omicron variants among 47 (32%) of 145 samples from travellers during the start of the omicron spread in Ghana (wave 4). INTERPRETATION: This study shows the value of repurposing existing influenza surveillance platforms to monitor SARS-CoV-2. Influenza continued to circulate in Ghana in 2020 and 2021, and remained a major cause of severe acute respiratory illness. We detected importations of SARS-CoV-2 variants into Ghana, including those that did or did not lead to onward community transmission. Investment in strengthening national influenza surveillance platforms in low-income and middle-income countries has potential for ongoing monitoring of SARS-CoV-2 and future pandemics. FUNDING: The EDCTP2 programme supported by the EU.