Drug resistance is one of the main reasons for cancer treatment failure, leading to a rapid recurrence/disease progression of the cancer. Recently, artificial intelligence (AI) has empowered physicians to use its powerful data processing and pattern recognition capabilities to extract and mine valuable drug resistance information from large amounts of clinical or omics data, to study drug resistance mechanisms, to evaluate and predict drug resistance, and to develop innovative therapeutic strategies to reduce drug resistance. In this review, we proposed a feasible workflow for incorporating AI into tumor drug resistance research, highlighted current AI-driven tumor drug resistance applications, and discussed the opportunities and challenges encountered in the process. Based on a comprehensive literature analysis, we systematically summarized the role of AI in tumor drug resistance research, including drug development, resistance mechanism elucidation, drug sensitivity prediction, combination therapy optimization, resistance phenotype identification, and clinical biomarker discovery. With the continuous advancement of AI technology and rigorous validation of clinical data, AI models are expected to fuel the development of precision oncology by improving efficacy, guiding therapeutic decisions, and optimizing patient prognosis. In summary, by leveraging clinical and omics data, AI models are expected to pioneer new therapy strategies to mitigate tumor drug resistance, improve efficacy and patient survival, and provide novel perspectives and tools for oncology treatment.