The Internet is a primary breeding ground for various network attacks, presenting a persistent challenge to cybersecurity. Machine learning has emerged as a powerful tool for automating the detection of cyber attacks and threats. Unlike traditional algorithms that rely on predefined signatures or rules, machine learning excels at uncovering complex patterns within vast volumes of Internet data. This capability enables the development of more intelligent and effective security solutions. The integration of machine learning into security systems has become a critical focus in both academia and industry. Nevertheless, the integration of machine learning and cybersecurity remains in its infancy. A significant gap exists between theory and practice: while machine learning may perform well in controlled or simulated environments, it may not work as expected in complex and dynamic real-world scenarios. Currently, machine learning security solutions are often evaluated using publicly available datasets in controlled laboratory settings. These lab-based evaluations introduce uncertainty about their practical effectiveness, which may hinder their adoption by security practitioners in real-world contexts. Proactive security measures aim to prevent threats before they cause harm, offering greater efficiency and effectiveness compared to reactive security, which relies on responsive strategies. Machine learning can enhance proactive security by automatically identifying potential vulnerabilities and predicting emerging threats, thereby strengthening the protection of Internet infrastructures. This dissertation aims to facilitate the application of machine learning in real-world cybersecurity settings, with a focus on addressing five core research questions: 1) What general challenges and limitations arise in the design, development, and deployment of practical ML-based security applications? 2) How can ML-based security solutions be effectively implemented in real-world scenarios? 3) What specific challenges and limitations are encountered when implementing such solutions in practical environments? 4) What current technologies, approaches, or solutions can be used to address these challenges and limitations, thereby facilitating the implementation of practical ML-based security systems? 5) What future research directions hold promise for advancing the practical application of machine learning in the cybersecurity field? We begin with a comprehensive literature review, identifying potential challenges and limitations in the practical application of machine learning (ML) within the field of cybersecurity. Building on these insights, we develop two practical tools designed to enhance existing proactive security mechanisms, directly addressing specific real-world challenges. Subsequently, we offer key recommendations regarding methodologies and solutions to mitigate obstacles in the development and deployment of realistic ML-based security systems. Finally, we propose future research directions, highlighting promising technologies and concepts with the potential to advance the field of practical ML applications in cybersecurity. This dissertation represents the first comprehensive investigation into the application of machine learning in realistic cybersecurity scenarios, with significant implications for the field of ML-based cybersecurity. It provides security researchers and practitioners with a deeper understanding of practical challenges and obstacles in this field. The development of two practical tools not only advances state-of-the-art proactive security mechanisms but also delivers actionable recommendations to assist researchers in addressing these challenges. Finally, the proposed future research directions highlight the potential of emerging technologies to enable more effective ML-driven security solutions in real-world environments. Overall, the insights presented in this dissertation help bridge the gap between theory and practice in ML-based cybersecurity, promoting the practical implementation of ML security systems that can replace or complement traditional approaches.