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Supercritical CO₂ extraction (SCCO₂) extraction of cannabis oil from Indian cannabis (<i>Cannabis indica</i>) leaves was optimized through a central composite design using CO₂ pressure (150–250 bar), temperature (30–50 °C) and time (1–2 h). From the regression model, the optimal CO₂ pressure, extraction temperature and time were 250 bar, 43 °C and 1.7 h, respectively resulting in the experimental yield of 4.9 wt% of cannabis oil via SCCO₂ extraction. The extract contained cannabidiol, tetrahydrocannabivarin, Δ⁹-tetrahydrocannabinol and Δ⁸-tetrahydrocannabinol as well as two terpenoids such as cis-caryophyllene and α-humulene. Besides SCCO₂ extraction of cannabis oil, the raffinate biomass was utilized to extract polyphenols using water as the extraction medium. Cannabis oil and water extractive were investigated for their half-maximal inhibitory concentration (IC₅₀) values, which were found to be 1.3 and 0.6 mg/mL, respectively. This is comparable to the commercially available antioxidant such as butylated hydroxytoluene with an IC₅₀ value of 0.5 mg/mL. This work on SCCO₂ extraction of cannabinoids and other valuable bioactive compounds provides an environmentally sustainable technique to valorize cannabis leaves.