Bioactive compounds benefit significantly from PEGylation in both pharmacological and biological applications. The most popular technique for giving drug nanocarriers stealth characteristics is now “PEGylation.” Target-site drug delivery systems are becoming more popular in the pharmaceutical industry because of their many benefits, including greater bioavailability and increased drug dosage capacity. However, specific current issues must be resolved. The interplay between drug delivery systems and blood proteins serves as one example. Based on alterations to the polyethylene glycol surface, this problem has a strong candidate. The most well-known and complex technique to create drug delivery systems with an extended blood circulation period is the surface coating of different medicinal nanocarriers with polyethylene glycol. For drug-loaded nanocarriers to effectively accumulate in target organs or tissues, prolonged circulation is often necessary. Targeted distribution is made possible by polyethylene glycol’s protection against potential exterior interactions with other chemicals. These innovative methods can help cure diseases like cancer, diabetes, hemophilia, and pain. This research examines key polyethylene glycol and other polymer characteristics that can be leveraged to create long-circulating nanocarriers. This review also includes descriptions of PEGylated liposomes, metal nanoparticles, polymeric nanoparticles, and other drug delivery systems. This strategy is expected to offer more viable and valuable applications soon.