Respiratory tract infections (RTIs) are frequent ailments among humans and are a high burden on public health. This study aimed to determine thein vitroantibacterial, anti-inflammatory, and cytotoxic effects of indigenous medicinal plants used in the treatment of RTIs, namely,Senna petersiana,Gardenia volkensii,Acacia senegal, andClerodendrum glabrum. Dried leaves were extracted using various organic solvents. Antibacterial activity was quantified using the microbroth dilution assay. Protein denaturation assays were used to evaluate anti-inflammatory activity. The cytotoxicity of the extracts towards THP-1 macrophages was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity was determined using free radical scavenging activity and ferric-reducing power. Total polyphenolics were quantified. Liquid chromatography mass spectrometry was used to evaluate the acetone plant extracts. Nonpolar extracts had noteworthy antibacterial activity againstStaphylococcus aureus,Escherichia coli,Pseudomonas aeruginosa, andMycobacterium smegmatiswhere MIC values ranged between 0.16 and 0.63 mg/mL. At 100μg/mL,A. senegal,G. volkensii, andS. petersianahad a nonsignificant effect on the viability of the THP-1 macrophages. The LC-MS analysis of the leaf extracts ofS. petersianadetectedColumnidin,Hercynine, L-Lysine citrate, and Gamma-Linolenate. A pentacyclic triterpenoid, cochalate, was detected inG. volkensii.Two flavonoids 7-hydroxy-2-(4-methoxyphenyl)-4-oxo-chroman-5-olate and (3R)-3-(2,4-dimethoxyphenyl)-7-hydroxy-4-oxo-chroman-5-olate were detected in theC. glabrumextract. The findings from this study indicated that the leaves of the selected plant extracts possess antioxidant, anti-inflammatory, and antibacterial activity. Therefore, they may serve as good candidates for further pharmaceutical investigations.