Objective The present study aims to evaluate the effects of posture, task, and handgrip style on discomfort, neck kinematics, and concomitant muscular activity when using a smartphone (SP). Background Along with the popularity of smartphones, musculoskeletal disorders have become prevalent among smartphone users. However, comprehensive aspects of discomfort, kinematics, and electromyographic responses across various conditions remain to be investigated. Method Twenty-four young smartphone users performed typing, video watching, and reading tasks while holding the smartphone both with one hand and with two hands while either sitting or standing. Neck kinematics and muscular activities were simultaneously recorded. Results Working with SPs led to higher discomfort in the neck ( p = 0.01), lower back ( p = 0.01), and shoulder ( p = 0.04) while sitting as compared to standing. Sitting was associated with greater neck flexion and more minor lateral bending for all tasks and grip styles ( p < 0.05). Electromyographic analysis indicated significant differences between sitting and standing, with alterations being dependent on the test condition. Moreover, neck kinematics and muscular activities significantly differed based on the task nature, handgrip, and interactions. Conclusion This study highlights the risk of using smartphones in increased neck angle flexion and muscular activities fatigue. Thus, posture and handgrip should be considered while using SPs. As each test condition affects a specific dependent variable, a holistic approach is required to evaluate the responses of SP users’ musculoskeletal systems. Application Results can be applied to develop guidelines for musculoskeletal disorders/discomfort prevention among SP users, especially with the rise of smartphone use during the COVID-19 pandemic.