<p>Tretinoin (TRE) is widely used in topical treatments, but its stability and therapeutic efficacy are often limited. To overcome these challenges, encapsulating TRE in niosomes may improve its stability and therapeutic outcomes. This study aims to enhance the stability and therapeutic efficacy of TRE by encapsulating it in niosomes for topical applications. Niosomes were prepared using the nanoprecipitation method and characterized for particle size, zeta potential, and encapsulation efficiency. The antioxidant activity of niosomal TRE was evaluated through the DPPH assay. Two cream formulations containing niosomes, one with hyaluronic acid (HA) and the other with carboxymethyl cellulose (CMC), were assessed for drug release, rheological properties, and stability under various storage conditions. The optimized niosomal formulation demonstrated a particle size of 503 nm, a zeta potential of − 21.6 mV, and an encapsulation efficiency of 90%. Niosomal TRE exhibited superior antioxidant activity compared to free TRE. The HA-based cream showed better drug release kinetics, higher flux, and enhanced spreadability compared to the CMC-based cream. Both cream formulations maintained stability under different storage conditions. Although the HA-based formulation demonstrated improved performance compared to the CMC-based formulation, further statistical analysis is required to confirm the significance of these differences. Niosomal systems may increase tretinoin’s stability and topical distribution, but more in vivo and clinical research is needed to validate these results.</p> Graphical Abstract <p>The illustration shows the niosomal encapsulation of tretinoin, DLS characterization (size and zeta potential), comparative release kinetics from CMC and HA creams (Higuchi model and flux), and in vivo skin irritation results in BALB/c mice.</p> <p></p>