Mandhana reached the landmark during India's Women's Asia Cup clash against Hong Kong when she smashed a huge six off Ruchitha Venkatesh in the 18th over to move past Mithali's tally of 10,868 international runs.
Mandhana surpasses Mithali Raj
Mandhana eventually fell for a breathtaking 124, taking her career international tally to 10,880 runs and moving to the top of the all-time women's international run-scoring chart.
Mithali Raj is now second with 10,868 runs, followed by New Zealand's Suzie Bates (10,740), England's Charlotte Edwards (10,273) and West Indies' Stafanie Taylor (10,007).
The milestone capped a remarkable day for Mandhana, who continued to dominate despite Hong Kong's attempts to contain her with a wide bowling line.
Record-breaking 124 in Dubai
Mandhana's 124 is now the highest individual score in Women's T20 Asia Cup history, surpassing Chamari Athapaththu's unbeaten 119 against Malaysia in 2024.
Her innings featured seven sixes and 14 boundaries, with Mandhana finding gaps and clearing the ropes with remarkable ease on a surface where other batters initially struggled.
She also became the first Indian batter to score two centuries in Women's T20Is.
Mandhana breaks Lanning's century record
The India opener added another major record to her name when she brought up her 18th international century in the 17th over.
With that hundred, Mandhana moved ahead of Australian great Meg Lanning, who has 17 international centuries.
Mandhana's 18 centuries are now the most by any batter in women's international cricket.
India batters join the charge
Mandhana's opening partner Shafali Verma initially took time to settle before breaking loose during the final over of the powerplay, which yielded 22 runs.
Pratika Rawal, batting at No. 3 in her debut T20I series, made 10 off 12 balls before being caught at cover while attempting to accelerate.
India captain Harmanpreet Kaur scored 10 off nine balls, while Richa Ghosh made 11 off 13 before both were dismissed attempting aerial shots.
Mandhana, however, remained the centrepiece of India's innings, producing a landmark knock that saw her rewrite several chapters of women's international cricket in a single evening.