Pydrax is a densely populated genus in the Rubiaceae plant family, with about a hundred and thirty species. Some Psydrax species are used in traditional medicine as remedies for different diseases and have also been investigated for biological activities and phytochemicals. However, Psydrax manensis (Aubrév. & Pellegr.) Bridson, to the best of our knowledge, has not received any scientific evaluation of its chemical constituents nor bioactivities, and it is not used in traditional medicine. The antimicrobial properties of methanol extract and hexane, ethyl acetate, and butanol fractions of P. manensis leaves against two Gram-positive and Gram-negative bacteria and two fungal species were assessed using agar well diffusion and agar dilution methods for preliminary antimicrobial assay and MIC determination, respectively. In addition, the extract and fractions were screened for major phytochemical classes using standard methods. The antimicrobial result showed that Pseudomonas aeruginosa was the most susceptible to the test samples (MIC: 0.13 mg/mL) among the bacterial species tested, while fungal species were more resistant to the test samples than the test bacteria. Candida albicans was inhibited by ethyl acetate fraction, while Aspergillus niger was susceptible to the butanol fraction. The qualitative phytochemical analysis showed that the crude extract contained flavonoids, polyphenols, glycosides, steroids, tannins, and terpenes but not alkaloids. The fractions shared the phytochemicals in the extract in varying degrees according to their polarity. The outcome of this study presents the extract and fractions of P. manensis leaves as potential sources of antimicrobial molecules.