<p>The development of second language (L2) proficiency relies heavily on listening. Despite this, the influence of topic familiarity on L2 listening comprehension has received relatively little empirical attention, and researchers continue to hold divergent perspectives on the effectiveness of listening strategies in facilitating the processing of spoken L2 input. To address the gap, this study aims to explore to what extent learners’ topic familiarity and listening strategy use influence L2 listening comprehension. Eighty-three Chinese learners of English were investigated through an L2 listening comprehension test and two questionnaires for topic familiarity and L2 listening strategy use. In addition, thirty-two of the participants took an interview to recall the listening strategy use during their listening test. Results revealed significant correlations between L2 listening comprehension and both topic familiarity and listening strategy use. Collectively, these predictors explained 23% of the variance in comprehension outcomes. Topic familiarity was found to explain more of the variance in L2 listening comprehension than listening strategy. We discussed pedagogical implications in L2 listening teaching and research.</p>