Camptothecin and its derivatives exhibit broad-spectrum antitumor activity, but their clinical application is hampered by poor water solubility, myelosuppression, and gastrointestinal toxicity. Peptide–drug conjugates (PDCs) represent the next generation of targeted therapeutic agents. In this study, we designed two RGDS-hydroxycamptothecin conjugates, 6-RGDS and 2-RGDS, which were linked via ester and ether bonds, respectively. The antitumor proliferation and anti-metastatic effects of these conjugates were evaluated. 6-RGDS exhibited significant antitumor activity both in vitro and in vivo, whereas the ether-linked 2-RGDS showed relatively lower activity. The RGDS tetrapeptide endowed the compound with favorable anti-tumor metastatic properties and also reduced gastrointestinal toxicity. Our findings suggested that RGDS-modified hydroxycamptothecin conjugates could overcome the limitations associated with camptothecin, offering a promising approach for more effective and safer antitumor therapies. Moreover, the presence of a cleavable ester bond, as seen in 6-RGDS, appears to be essential for the efficient release of active substances, thereby enhancing therapeutic efficacy.