Alpha thalassemia is an understudied disease that results from the insufficient production of the protein alpha globin. Alpha thalassemia is relatively understudied because of its relative scarcity in Western countries, as well as the lack of adult mouse models. Typically, severe alpha thalassemia results in embryonic lethality in mice and humans, limiting the available platforms for research. In this study we describe two novel models; one based on the transplantation of alpha knockout fetal liver cells, and a conditional knockout mouse model (cKO) that can recombine to eliminate the alpha globin genes in the presence of Cre recombinase. In the case of the cKO, isolated cells were treated with an anti-CD117 conjugated lipid nanoparticle containing Cre mRNA ex vivo before being transplanted into recipient mice. Furthermore, we developed a lentiviral vector capable of expressing human alpha globin (ALS20αI) with the intent of treating these models. Through the application of various analytical methods, including complete blood counts (CBC), high-performance liquid chromatography (HPLC), droplet digital PCR (ddPCR), and immunohistochemistry (IHC), we characterized both mouse models of alpha thalassemia and evaluated the ability of ALS20αI to ameliorate the observed phenotype. Both mouse models demonstrated a severe phenotype that resulted in lethality at approximately 7-8 weeks post-transplant. During this time mice demonstrated a gradually worsening phenotype characterized by increases in hematocrit, red blood cells, reticulocytes, erythropoietin expression, and beta globin tetramer formation. These models showed decreased hepcidin expression and the development of splenomegaly, iron overload in the liver, and sites of vessel occlusion in the lungs and brain. Treatment with ALS20αI resulted in amelioration of this phenotype and a rescue from lethality, as well as reducing the levels of hemoglobin H produced in primary cells of alpha thalassemic patients. These models promise to be powerful tools for the improvement of our understanding of alpha thalassemia, and the development of additional treatments, while ALS20αI has proven to be highly effective at ameliorating a novel and severe phenotype.