Somatic mutations in skin cancers and other ultraviolet (UV)-exposed cells are typified by C>T and CC>TT substitutions at dipyrimidine sequences; however, many oncogenic “driver” mutations in melanoma do not fit this UV signature. Here, we use genome sequencing to characterize mutations in yeast repeatedly irradiated with UV light. Analysis of ~50,000 UV-induced mutations reveals abundant non-canonical mutations, including T>C, T>A, and AC>TT substitutions. These mutations display transcriptional asymmetry that is modulated by nucleotide excision repair (NER), indicating that they are caused by UV photoproducts. Using a sequencing method called UV DNA endonuclease sequencing (UVDE-seq), we confirm the existence of an atypical thymine-adenine photoproduct likely responsible for UV-induced T>A substitutions. Similar non-canonical mutations are present in skin cancers, which also display transcriptional asymmetry and dependence on NER. These include multiple driver mutations, most prominently the recurrent BRAF V600E and V600K substitutions, suggesting that mutations arising from rare, atypical UV photoproducts may play a role in melanomagenesis. Display omitted •Genome sequencing of UV-irradiated yeast reveals non-canonical mutation classes•Non-canonical mutations are likely caused by atypical UV photoproducts•UV induces an atypical thymine-adenine (TA) photoproduct in vitro and in yeast cells•Non-canonical UV mutation classes can explain many driver mutations in melanoma UV mutagenesis has been well studied, but many driver mutations in melanoma do not fit the canonical UV signature. Using whole-genome sequencing, Laughery et al. show that UV induces a broader spectrum of mutations than anticipated. Non-canonical UV mutations are likely caused by atypical photoproducts, which may contribute to melanomagenesis.