Topotecan (TPT) is a semi-synthetic, water-soluble derivative of camptothecin, which inhibits the action of topoisomerase I in the S-phase of the cell cycle leading to cell death. For the effective delivery of TPT to cancer cells, pH-sensitive sialic acid modified liposomes were developed. These liposomes were prepared by the thin-film hydration method using the active loading technique. Vesicle size, polydispersity index (PDI), zeta potential, and percentage entrapment efficiency were determined to be 167 ± 3.78 nm, 0.243, -8.39 mV, and 79.88 ± 1.67%, respectively. The pH-sensitive sialic acid (SA) conjugated liposomes enhanced the drug release at acidic pH 4 (92.33 ± 4.21%) as compared to physiological pH 7.4 (63.11 ± 4.51%). A Sulforhodamine B (SRB) cytotoxicity assay was performed in Murine sarcoma S180 cell lines and the GI50 value of free TPT, Lipo, P-Lipo, SA-P-Lipo, and Adriamycin (ADR) were determined to be 10.07 ± 0.15, 27.33 ± 1.01, 28.76 ± 0.87, 15.7 ± 0.45, and 11.5 ± 0.21 µg/mL, respectively. Results obtained from the apoptosis study revealed that cell death by a combination of early apoptosis and apoptosis caused by SA-P-Lipo was ∼24 fold higher than the control. These results demonstrated that pH-sensitive sialic acid conjugated liposomes will be a potential formulation for improving the antitumor efficacy of TPT. However, further research is necessitated to expedite its applicability in clinical regimen in order to ascertain its safety and efficacy.