Lack of proper infrastructure and the poor economic conditions of rural communities make them dependent on herbal medicines. Thus, there is a need to obtain and conserve the historic and traditional knowledge about the medicinal importance of different plants found in different areas of the world. In this regard, a field study was conducted to document the medicinal importance of local plants commonly used by the inhabitants of very old historic villages in Southern Punjab, Pakistan. In total, 58 plant species were explored, which belonged to 28 taxonomic families, as informed by 200 experienced respondents in the study area. The vernacular name, voucher number, plant parts used, and medicinal values were also documented for each species. Among the documented species, Poaceae remained the most predominant family, followed by Solanaceae and Asteraceae. The local communities were dependent on medicinal plants for daily curing of several ailments, including asthma, common cold, sore throat, fever, cardiovascular diseases, and digestive disorders. Among the reported species, leaves and the whole plant remained the most commonly utilized plant parts, while extracts (38.8%) and pastes (23.9%) were the most popular modes of utilization. Based on the ICF value, the highest value was accounted for wound healing (0.87), followed by skincare, nails, hair, and teeth disorders (0.85). The highest RFC value was represented by Acacia nilotica and Triticum aestivum (0.95 each), followed by Azadirachta indica (0.91). The highest UV was represented by Conyza canadensis and Cuscuta reflexa (0.58 each), followed by Xanthium strumarium (0.37). As far as FL was concerned, the highest value was recorded in the case of Azadirachta indica (93.4%) for blood purification and Acacia nilotica (91.1%) for sexual disorders. In conclusion, the local inhabitants primarily focus on medicinal plants for the treatment of different diseases in the very old historic villages of Southern Punjab, Pakistan. Moreover, there were various plants in the study area that have great ethnobotanical potential to treat various diseases, as revealed through different indices.