Mutant p53 rescue by small molecules is a promising therapeutic strategy. In this structure-activity relationship study, we examined a series of adamantyl isothiocyanates (Ad-ITCs) to discover novel agents as therapeutics by targeting mutant p53. We demonstrated that the alkyl chain connecting adamantane and ITC is a crucial determinant for Ad-ITC inhibitory potency. Ad-ITC <b>6</b> with the longest chain between ITC and adamantane displayed the maximum growth inhibition in p53<sup>R280K</sup>, p53<sup>R273H</sup>, or p53<sup>R306Stop</sup> mutant cells. Ad-ITC <b>6</b> acted in a mutant p53-dependent manner. It rescued p53<sup>R280K</sup> and p53<sup>R273H</sup> mutants, thereby resulting in upregulating canonical wild-type (WT) p53 targets and phosphorylating ATM. Ad-ISeC <b>14</b> with selenium showed a significantly enhanced inhibitory potency, without affecting its ability to rescue mutant p53. Ad-ITCs selectively depleted mutant p53, but not the WT, and this activity correlates with their inhibitory potencies. These data suggest that Ad-ITCs may serve as novel promising leads for the p53-targeted drug development.