Can online learning strategies in general chemistry work as well as learning in an on-site classroom? As the COVID-19 pandemic restrictions eased in 2022, a cohort of first-year Chemistry majors took a general chemistry lecture course in hybrid mode: learning activities were undertaken online using a flipped classroom approach, while formal summative assessments were administered in-person. This "natural experiment" allowed comparison of this cohort's test results with those of prepandemic cohorts who took the course fully on-site. Final examination scores from a typical 2 h, proctored, closed-notes, and multiple-choice examination were compared with results from the prepandemic 2019 class and a class that used a similar "atoms first" topic sequence in 2015. All three sets of scores were similar, with means within the 95% confidence interval (standard error of the mean). Distributions of the scores showed similar medians, with overlapping second to third quartile ranges. Student perceptions of learning were surveyed using Student Assessment of Learning Gains (SALG) instruments. The survey results averaged from "good gain" to "great gain" across all course learning outcomes. Students rated the following resources as most helpful to their learning: (1) online quizzes with multiple attempts and immediate feedback, and (2) interactive anonymous recitation and discussion in synchronous class sessions using the web-based interactive presentation and audience response application Mentimeter. These emphasize the value of low-stakes learning from mistakes, contingent teaching, inclusivity, and the facilitation of metacognition. This "natural experiment", arising from pandemic-related challenges, shows that online classes using active learning strategies can be as effective as face-to-face classes.