Recent progression in investigational studies aiming to integrate natural products and plant oils in developing new dosage forms that would provide optimal therapeutic effect. Therefore, the aim of the present exploration was to inspect the influence of jojoba oil in boosting the anti-inflammatory effect of colchicine natural product. To our knowledge, there is no formulation comprising colchicine and jojoba oil together to form a niosomal emulgel preparation anticipated for topical application. Colchicine is a natural product extracted from Colchicum autumnale that has been evidenced to show respectable anti-inflammatory activity. Owing to its drawbacks and low therapeutic index, it was preferable to be formulated into topical dosage form. The current study inspected colchicine transdermal delivery by developing niosomal preparation as a potential nanocarrier included into emulgel prepared with jojoba oil. Box Behnken design was constructed to develop 17 niosomal emulgel formulations. The optimized colchicine niosomal emulgel was evaluated for its physical characteristics and in vitro release studies. The in vivo anti-inflammatory activity was estimated via carrageenan-induced rat hind paw edema method. The developed colchicine niosomal preparation revealed particle size of 220.7 nm with PDI value 0.22, entrapment efficiency 65.3%. The formulation was found to be stable showing no significant difference in particle size and entrapment efficiency up on storage at 4 °C and 25 °C for 3 months. The optimized colchicine niosomal emulgel exhibited a pH value 6.73, viscosity 4598 cP, and spreadability 38.3 mm. In vitro release study of colchicine from niosomal emulgel formulation was around 52.4% over 6 h. Apparently, the proficient anti-inflammatory activity of colchicine niosomal emulgel was confirmed via carrageenan-induced rat hind paw edema test. Overall, the results recommend the combination of niosomal preparation with jojoba oil-based emulgel that might signify a favorable delivery of anti-inflammatory drug such as colchicine.