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Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on <i>T. congolense</i> infection and its inhibitory effects on the partially purified <i>T. congolense</i> sialidase and phospholipase A₂ (PLA₂) were investigated. Treatment with phloroglucinol for 14 days significantly (<i>p</i> < 0.05) suppressed <i>T. congolense</i> proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against <i>T. congolense</i>-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream <i>T. congolense</i> sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA₂ (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of −4.9 and −5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA₂ respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (−67.84 ± 0.50 kJ/mol) than PLA₂-phloroglucinol complex (−77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA₂-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA₂.