An attractive feature of human VHs over camelid VHHs as immunotherapeutics is their perceived lower risk of immunogenicity. While human VHs can readily be obtained from synthetic phage display libraries, they often suffer from low affinity and poor solubility compared to VHHs derived from immune libraries. Using SARS-CoV-2 spike protein as a model antigen, we screened a synthetic human VH phage display library and identified a diverse set of antigen-specific VHs. However, the VHs exhibited low affinity, and many had low solubility; that is, they were prone to aggregation. To explore the feasibility of improving the affinity, we subjected a representative VH to in vitro affinity maturation. We created a yeast surface display library of VH variants employing a site-saturated mutagenesis approach targeting complementarity-determining regions and selected against the target antigen. Next-generation sequencing of the selected variants, combined with structural modeling, identified a set of VHs as potentially improved candidates. Characterization of these candidates revealed several VHs with improved affinities of up to 100-fold (KDs as low as 3 nM) and potent neutralization capabilities; however, they still showed significant aggregation. By introducing as few as two camelid residues into the framework region 2 of a high-affinity VH (a process referred to as camelization), we were able to completely solubilize the VH without compromising its affinity and other important attributes, including thermostability and protein A binding. This study demonstrates the feasibility of generating high-affinity, -solubility, and -stability human VHs from synthetic libraries through a combination of in vitro affinity maturation and minimal camelization.