Conventional drug formulations release active pharmaceutical ingredients (APIs) immediately after administration, while long-acting (LA) drug products are designed for prolonged therapeutic effects, thereby reducing administration frequency and improving patient compliance. The development of LA therapeutics for chronic disease treatment has significantly helped patients adhere to their regimens, reducing the need for daily doses and easing the burden on healthcare systems. Advances in treatment have transformed Human Immunodeficiency Virus (HIV) into a manageable chronic disease, and efforts are underway to eliminate HIV in the future. Nowadays, antiretroviral therapies (ARTs) are widely available and accessible, daily oral pre-exposure prophylaxis (PrEP) has been highly effective and the new LA ARTs and LA PrEP are being actively pursued. The development of LA antiretrovirals for HIV has revolutionized the landscape of global implementation of HIV prevention and treatment. This article provides an overview of LA medicines (pills, injections, solid implants, and in situ forming depots) for the prevention and treatment of HIV from a pharmaceutics perspective, describing approved medicines, recognizing promising technologies, and discussing the pros and cons of poly (lactic-co-glycolic acid) (PLGA) particles, liposomes, hydrogels, and organogel formulations.