Drug resistance is considered a key reason behind the failure of therapeutic medications in treating chronic diseases, including hypertension, cancer therapeutics, and antimicrobial agents. Among the strategies used to overcome drug resistance are therapeutic targeting of other factors involved in altered biochemical or pharmacological pathways or targeting the resistance factors themselves. There are numerous factors beyoned drug resistance; P-glycoprotein (P-gp) and multidrug resistance proteins are among the most causative factor for drug resistance development. Herein, this review is concerned with the character of pharmaceutical polymers as P-gp inhibitors and how modifying their physicochemical properties could compromise the efflux and transport characteristics of P-gps. A wide range of P-gp inhibitors are available, including designed chemicals, pharmaceutical excipients, and formulations. Chitosan, Soluplus®, Poloxamers, polyethylene glycols, dendrimers, anionic gums, sodium alginate, and other functionalized polymers could be harnessed as drug delivery tools through their promising effect on P-gp. Additionally, we discussed the use of pharmaceutical polymers in a variety of therapies by leveraging their exceptional physicochemical properties, which enhance their bioavailability, antimicrobial activity, and anticancer properties.