Kigelia africana is used to manage inflammation among indigenous communities. We hypothesized that K. africana extracts contain phytoconstituents with good antioxidant and anti-inflammatory activities. The methanolic extract of K. africana fruits and Spathodea campanulata leaves (SPK04), K. africana aqueous fruit extract (KFM02), and K. africana acetone fruit extract (KFM05) were subjected to antioxidant and anti-inflammatory assays. Antioxidant activity was evaluated using the ABTS radical scavenging assay, and the MTT cell viability assay was used for cytotoxicity. The extracts were preincubated with enzymes and assayed for 15-LOX and COX-2 enzyme activity using an ELISA method. Nitric oxide (NO) inhibitory effect of the extracts was evaluated and measurement of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and the anti-inflammatory cytokine (IL-10) was done using ELISA kits. SPK04 had the highest antioxidant activity with a mean inhibition of 99.37 ± 0.56% and an IC50 of 4.28 µg/mL. SPK04 and KFM05 did not inhibit 15-LOX as their IC50 values were >1000 μg/mL. All extracts were safe on Vero cells at the highest concentration (200 µg/mL) tested. KFM02 was the best inhibitor of NO production and had the highest cell viability at both the lowest (50 µg/mL) and highest concentrations (200 µg/mL). SPK04 was the best COX-2 inhibitor while KFM05 expressed the strongest suppression effect for IL-β and IL-6. KFM02 did not inhibit IL-6 at the highest concentration (200 µg/mL). The order of suppression of TNF-α by the extracts differed across concentrations, KFM05 > SPK04 > KFM02 at 200 µg/mL, KFM02 > SPK04 > KFM05 at 100 µg/mL, and SPK04 > KFM02 > KFM05 at 50 µg/mL. All the tested extracts had no inhibitory effect against IL-10. SPK04, KFM05, and KFM02 had good antioxidant and anti-inflammatory activity and this supports their use as potential anti-inflammatory therapies. This study presents for the first time the antioxidant and anti-inflammatory activity of K. africana and S. campanulata polyherbal extract. It is also among the very few studies that have reported the inhibitory effect of cytokines IL-1β, TNF-α, IL-6, and IL-10 by K. africana.