Psoriasis is a chronic immune-mediated disease presented by erythematic lesions. It is an incurable disease; however, topical treatment attempts to stop the uncontrolled proliferation of skin cells. Quercetin (Qc) is a natural compound plentiful in several natural plant species and plays a vital role in treating psoriasis; however, it has poor aqueous solubility and penetrability. Consequently, our work aims to enhance Qc's dissolution and anti-psoriatic activity. In this work, Qc was isolated from Psidium guajava leaves, and spanlastics were prepared using the ethanol injection method. The % encapsulation efficiency (%EE) of Qc ranged from 76.40 ± 1.42 to 98.29 ± 0.2,4, and the Particle size (P.size) varied between 414.66 ± 1.94 to 748.33 ± 5.19 nm. In vitro release studies of Qc from spanlastic preparations were significantly higher than those from free drug dispersion. Selected Qc spanlastics formulation was included in Sodium carboxymethylcellulose (SCMC) 3.5% gel for biological application. Clinical improvement after eight weeks of treatment was powerfully distinguished. By the end of 8 weeks of treatment, Psoriasis Area and Severity Index (PASI) score decreased from 5.19 ± 1.14 at baseline to 2.26 ± 1.1. Qc is famous for its apoptotic-inducing activity, livin is one of the Inhibitors of apoptosis proteins (IAPs), and its function is mediated through the inhibition of caspase activation. Quantitative real-time polymer chain reaction (qrt- PCR) declared that the expression of livin (p = 0.002) was lowered while that of caspase-9 (P < 0.001) was elevated in comparison to those before treatment with QC spanlastics; thus, Qc spanlastics are promising easily prepared formulation for the treatment of psoriasis.