Learning through games in general and educational escape-rooms in particular requires participants to be creative and critical thinkers, work in collaboration with others, formulate an array of thinking strategies, and be familiar with media and technology. A specially designed chemistry-themed escape-room was built as an alternative learning and assessment environment. The goal of this research was to examine students' game-based experience and identify and characterize the skills and knowledge students experienced they used while in the escape-room. The study included 58 participants from chemistry-related departments who were either undergraduate or graduate students. The study applied the one-group posttest design, in which the learning outcomes are measured after a non-randomized group of participants is exposed to intervention. A questionnaire with closed-ended and open-ended questions was used to collect data. The findings indicated positive results regarding students' application of communication, collaboration, and high thinking abilities (21st-century skills). Students enjoyed the activity and felt motivated to learn chemistry. Although they found the activity challenging, the degree of enjoyment and motivation to learn chemistry was high. Our study contributes to the growing body of knowledge on game-based learning by addressing some of the gaps related to the use of escape-room environments in educational settings. It shows how students benefit from these environments, which foster their content knowledge in chemistry and develop their collaboration, communication, and higher-order thinking skills.