PDE4 inhibitors are effective therapeutic agents for various inflammatory diseases. Roflumilast, apremilast, and crisaborole have been developed and approved for the treatment of chronic obstructive pulmonary disease, psoriatic arthritis, and atopic dermatitis. Inflammation underlies many vascular diseases, yet the role of PDE4 inhibitors in these diseases remains inadequately explored. This review elucidates the clinical applications and anti-inflammatory mechanisms of PDE4 inhibitors, as well as their potential protective effects on vascular diseases. Additionally, strategies to mitigate the adverse reactions of PDE4 inhibitors are discussed. This article emphasizes the need for further exploration of the therapeutic potential and clinical applications of PDE4 inhibitors in vascular diseases. PDE4 is primarily present in immune cells, epithelial cells, and brain cells, acting as an intracellular non-receptor enzyme that regulates inflammation and epithelial integrity. Inhibiting PDE4 increases cyclic adenosine monophosphate (cAMP) levels, thereby regulating various genes and proteins to exert multiple effects and functions. Currently, PDE4 is regarded as a promising and effective therapeutic target for pulmonary diseases, skin diseases, and neurological disorders. Over the past few decades, numerous PDE4 inhibitors have been designed and synthesized. Roflumilast, apremilast, and crisaborole are approved for treating inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. However, the efficacy of these drugs is often accompanied by adverse reactions, including nausea, vomiting, and gastrointestinal disturbances. With the continuous development of drugs, PDE4 inhibitors have partially mitigated adverse reactions and achieved improved efficacy. It is well established that PDE4 inhibitors play a crucial role in inflammation. Inflammation underlies the pathogenesis of many vascular diseases. However, the mechanism of PDE4 inhibitors in vascular diseases remains unclear. This review summarizes the roles of PDE4 inhibitors in inflammation and vascular diseases, and discusses prospects for mitigating the adverse reactions of these inhibitors. PDE4 inhibitors have been demonstrated as an effective therapeutic strategy for treating diseases such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis (AD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, neuropathy, depression, memory enhancement, and emesis. However, the clinical application of PDE4 inhibitors has been consistently hindered by their adverse reactions. Rolipram, a first-generation PDE4 inhibitor, was initially discovered by Schering AG in the early 1990s. It is considered to have potential in treating neurological disorders such as depression and cognitive dysfunction. Despite its potential pharmacological effects, it has a narrow therapeutic window. Adverse reactions frequently occur during clinical trials, such as nausea, vomiting, and headache. The adverse reactions of rolipram have restricted its clinical use. RofPDE4 inhibitors are effective therapeutic agents for various inflammatory diseases. Roflumilast, apremilast, and crisaborole have been developed and approved for the treatment of chronic obstructive pulmonary disease, psoriatic arthritis, and atopic dermatitis. Inflammation underlies many vascular diseases, yet the role of PDE4 inhibitors in these diseases remains inadequately explored. This review elucidates the clinical applications and anti-inflammatory mechanisms of PDE4 inhibitors, as well as their potential protective effects on vascular diseases. Additionally, strategies to mitigate the adverse reactions of PDE4 inhibitors are discussed. This article emphasizes the need for further exploration of the therapeutic potential and clinical applications of PDE4 inhibitors in vascular diseases. PDE4 is primarily present in immune cells, epithelial cells, and brain cells, acting as an intracellular non-receptor enzyme that regulates inflammation and epithelial integrity. Inhibiting PDE4 increases cyclic adenosine monophosphate (cAMP) levels, thereby regulating various genes and proteins to exert multiple effects and functions. Currently, PDE4 is regarded as a promising and effective therapeutic target for pulmonary diseases, skin diseases, and neurological disorders. Over the past few decades, numerous PDE4 inhibitors have been designed and synthesized. Roflumilast, apremilast, and crisaborole are approved for treating inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. However, the efficacy of these drugs is often accompanied by adverse reactions, including nausea, vomiting, and gastrointestinal disturbances. With the continuous development of drugs, PDE4 inhibitors have partially mitigated adverse reactions and achieved improved efficacy. It is well established that PDE4 inhibitors play a crucial role in inflammation. Inflammation underlies the pathogenesis of many vascular diseases. However, the mechanism of PDE4 inhibitors in vascular diseases remains unclear. This review summarizes the roles of PDE4 inhibitors in inflammation and vascular diseases, and discusses prospects for mitigating the adverse reactions of these inhibitors. PDE4 inhibitors have been demonstrated as an effective therapeutic strategy for treating diseases such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis (AD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus, neuropathy, depression, memory enhancement, and emesis. However, the clinical application of PDE4 inhibitors has been consistently hindered by their adverse reactions. Rolipram, a first-generation PDE4 inhibitor, was initially discovered by Schering AG in the early 1990s. It is considered to have potential in treating neurological disorders such as depression and cognitive dysfunction. Despite its potential pharmacological effects, it has a narrow therapeutic window. Adverse reactions frequently occur during clinical trials, such as nausea, vomiting, and headache. The adverse reactions of rolipram have restricted its clinical use. Rof