Maerua triphylla root extracts are used by Maasai and Kikuyu communities in Kenya to manage headaches, stomachaches, migraines, and rheumatism. However, scientific data on their safety and efficacy are limited. The current study aims to investigate the safety, phytochemical constituents, analgesic, and anti-inflammatory activities of M. triphylla root extracts. Aqueous and methanol M. triphylla root extracts were prepared by cold maceration, and the extracts’ safety was evaluated using Wistar rats according to the Organization for Economic Cooperation and Development (2008) guidelines. Standard qualitative phytochemical screening methods were used for the detection of various phytochemical groups in the extracts. Analgesic activity assay in Swiss albino mice was done using the acetic acid-induced writhing test, while anti-inflammatory activity was determined in Wistar rats using the acetic acid-induced paw edema method. The methanol and aqueous extracts revealed LD50 > 2000 mg/kg bw, classifying them as nontoxic. The presence of cardiac glycosides, flavonoids, alkaloids, and phenols was observed in both extracts. However, saponins were only present in the methanol extract. In the analgesic study, mice that received 100 mg/kg bw and 500 mg/kg bw of aqueous root extract of M. triphylla had significantly lower acetic acid-induced writhing than mice that received acetylsalicylic acid 75 mg (reference drug) ( p < 0.05 ). Additionally, mice that received 500 mg/kg bw of methanol root extract of M. triphylla had significantly lower acetic acid-induced writhing than mice that received the acetylsalicylic acid 75 mg ( p < 0.05 ). In the anti-inflammatory study, there was no significant difference ( p < 0.05 ) between the inhibitory activity of different doses of the aqueous root extract of M. triphylla and a 50 mg/kg dose of diclofenac sodium (reference drug) on acetic acid-induced paw edema in rats. Moreover, there was no significant difference in the inhibitory activity of 100 mg/kg bw and 500 mg/kg bw doses of the methanol root extract of M. triphylla and a 50 mg/kg dose of diclofenac sodium on acetic acid-induced paw edema ( p > 0.05 ). These findings suggest that the roots of M. triphylla may be useful in the safe mitigation of pain and inflammation and therefore support their ethnomedicinal use in the management of pain and inflammation.