Human African trypanosomiasis, also known as sleeping sickness, is caused by the single-celled kinetoplastid parasite Trypanosoma brucei transmitted to humans by infected tsetse flies. The disease threatens millions of people. Currently available treatment options are faced with some important challenges. In this work, a total of eighty-seven (87) morpholine derivatives were evaluated for drug-likeness based on Lipinski’s rule of five and their ability to inhibit the activities of trypanosomal triosephosphate isomerase was assessed by molecular docking and calculation of free energy of binding. Analysis of the results revealed that 97.7 % of the dataset complied with Lipinski’s criteria for a molecule to be orally bioavailable. Also, 50.0 % of the studied compounds had a good total polar surface area profile, a parameter which is of great importance for the treatment of stage two Trypanosoma infections. Docking studies showed that all the dataset demonstrated affinity for triosephosphate isomerase. Moreover, six morpholines scored higher than the co-crystallized inhibitor of triosephosphate isomerase (2-phosphoglycerate). These derivatives inhibited the activity of triosephosphate isomerase by making significant interactions with Glu 167, Val 214, 233, Asn 11, Lys 13, Ser 213, Leu 232, Ile 172, Gly 211, 212, 234, 235 and His 92 in the active site of the protein. Furthermore, besides the acceptable pharmacokinetic profiles of the six morpholines, they also showed inhibitory potencies toward four other validated antitrypanosomal drug targets. In view of the foregoing findings, we propose that the six morpholine derivatives be given worthwhile attention to develop them into novel trypanocides.