Acquired resistance to endocrine therapy poses a major limitation in the treatment of estrogen receptor (ER)-positive breast cancer (BC). Somatic mutations of the ESR1 gene, which encodes ERα, are one of the key resistance mechanisms. However, the effect of mutations and especially double mutations on the binding of novel drugs remains insufficiently understood. To evaluate the effect of the mutations at the molecular level, a comprehensive computational approach was employed, including molecular docking, binding free energy calculations (MM-GBSA), and molecular dynamics simulations. A comparative analysis revealed opposite effects of ESR1 mutations on affinities of various selective ER degraders (SERDs). Vepdegestrant and fulvestrant were found to bind far less efficiently with ERα mutants and especially double mutants (e.g., Y537C/D538G) than with the native ERα. In contrast, the SERD ZB716 demonstrated the same or even better binding with most mutants. A potential structural cause of its resilience to mutations was identified via a comprehensive analysis, which included the evaluation of individual amino acid residue mobility through root-mean-square fluctuation (RMSF) calculations and an assessment of intermolecular hydrogen bond stability. ZB716 was shown to maintain a stable hydrogen bond with Glu353, and the bond was preserved in the ERα mutants. A lower stability of this key interaction was observed with fulvestrant. The findings elucidate the molecular mechanism of ESR1 mutation-driven resistance and support the promise of ZB716 as a compound capable of overcoming resistance conferred by a subset of the most common somatic ESR1 mutations in BC patients. The results justify the targeted design of new SERDs aimed at interacting with ERα mutants and outline an avenue of further research in the field of personalized therapy for ER+ BC.