Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the axial skeleton, causing intense pain, progressive joint destruction, and a gradual reduction in physical function. Additionally, AS can result in extra-musculoskeletal manifestations including inflammatory bowel disease (IBD), psoriasis, and acute anterior uveitis (AAU) affecting patients' quality of life (QoL). Furthermore, AS association with neurological and cardiovascular events has been documented. With the advent of biologics, treating AS has dramatically changed due to their high efficacy and tolerable safety. Nevertheless, there are differences in traits, including rapidity of onset, long-term efficacy, safety profile, and influence on comorbidities. A better understanding of such traits enables clinicians to make the best decision for each patient, increasing persistence, extending medication survival, enhancing patient satisfaction, and reducing the disease effect of AS. A review of the literature published in English in PubMed and Google Scholar databases from 2010 to 2023 was conducted. All relevant results fitting the scope of the topic were included. In this article, we emphasize biologics' efficacy and safety profile in patients with AS. In addition, we discuss the impact of biologics on comorbidities and health-related quality of life (HRQoL).