The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer respond to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment and is caused by genomic deletions and promoter methylation. Moreover, genes upregulated in PARPi-resistant cells and tumours predominantly consist of innate immune response genes, including ISG15 and factors of the ISGylation machinery. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug exogenous and, conversely, that ISG15 overexpression in BRCA1-/- cells triggers PARPi resistance. Mechanistically, ISG15 is required in BRCA1-/- PARPi-resistant cells for replication fork progression and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.