The prevalence and distribution of endemic human coronaviruses (HCoVs) in Ghana remain poorly characterized, particularly in the post-COVID-19 pandemic era. We conducted a cross-sectional molecular and serological survey of 1,000 individuals from five rural and five urban communities in Ghana to assess the prevalence of HCoVs. Reverse transcriptase real-time PCR (RT-qPCR) assays targeted SARS-CoV-2, HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E, while serological assays evaluated IgG antibody responses against SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E Spike proteins. A broad pan-coronavirus RT-qPCR assay detected HCoV RNA in 6.7% of participants, with SARS-CoV-2 as the most frequent, followed by HCoV-229E, HCoV-HKU1, and HCoV-OC43; HCoV-NL63 was not detected. Serological analyses revealed widespread exposure to SARS-CoV-2, HCoV-OC43, HCoV-229E, and HCoV-HKU1, with a low seroprevalence for HCoV-NL63. Our findings demonstrate ongoing co-circulation of multiple HCoVs in both rural and urban settings in Ghana post Covid-19, suggesting sustained community transmission, increased potential for co-infection, and the need for continued surveillance of endemic and emerging respiratory viruses. The data provides rare insights into the epidemiology of HCoVs in West Africa.